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Guzman-Castillo A, Vicente B, Schmidt K, Moraga-Escobar E, Rojas-Ponce R, Lagos P, Macaya X, Castillo-Navarrete JL. Interaction of Val66Met Brain-Derived Neurotrophic Factor and 5-HTTLPR Serotonin Transporter Gene Polymorphisms with Lifetime Prevalence of Post-Traumatic Stress Disorder in Primary Care Patients. Genes (Basel) 2024; 15:1355. [PMID: 39596555 PMCID: PMC11593576 DOI: 10.3390/genes15111355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/08/2024] [Accepted: 10/12/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: Post-traumatic stress disorder (PTSD) is a complex condition influenced by both genetic and environmental factors. This longitudinal study aimed to explore the connection between two specific genetic polymorphisms, Val66Met and 5-HTTLPR, and the lifetime prevalence of PTSD in patients from primary care settings. We also examined the role of sociodemographic and psychosocial factors to provide a more comprehensive view of PTSD risk. Methods: We recruited a cohort of primary care patients and diagnosed PTSD using a standardized diagnostic interview. Genetic analyses focused on Val66Met and 5-HTTLPR polymorphisms. We applied logistic regression to assess the association between these genetic markers and PTSD, considering factors such as gender, family history of depression, and experiences of childhood maltreatment. Results: Our findings show that women, individuals with a family history of depression, and those exposed to childhood maltreatment have a higher risk of developing PTSD. While the Val66Met polymorphism was not significantly associated with PTSD, the 5-HTTLPR polymorphism showed a marginal relationship. No significant interaction was found between the two polymorphisms in relation to PTSD. Conclusions: This study underscores the multifactorial nature of PTSD, influenced by both genetic and environmental factors. The findings point to the importance of further research on genetic predispositions and highlight the value of early interventions for high-risk populations in primary care settings.
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Affiliation(s)
- Alejandra Guzman-Castillo
- Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Av. Alonso de Ribera 2850, Concepción 4090541, Chile;
- Programa de Neurociencia, Psiquiatría y Salud Mental, NEPSAM (http://nepsam.udec.cl), Universidad de Concepción, Barrio Universitario s/n, Casilla 160-C, Concepción 4070386, Chile; (B.V.); (K.S.); (E.M.-E.); (R.R.-P.); (X.M.)
| | - Benjamín Vicente
- Programa de Neurociencia, Psiquiatría y Salud Mental, NEPSAM (http://nepsam.udec.cl), Universidad de Concepción, Barrio Universitario s/n, Casilla 160-C, Concepción 4070386, Chile; (B.V.); (K.S.); (E.M.-E.); (R.R.-P.); (X.M.)
- Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Av. Juan Bosco s/n 3er Piso, Box 160-C, Concepción 4070529, Chile
| | - Kristin Schmidt
- Programa de Neurociencia, Psiquiatría y Salud Mental, NEPSAM (http://nepsam.udec.cl), Universidad de Concepción, Barrio Universitario s/n, Casilla 160-C, Concepción 4070386, Chile; (B.V.); (K.S.); (E.M.-E.); (R.R.-P.); (X.M.)
- Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Av. Juan Bosco s/n 3er Piso, Box 160-C, Concepción 4070529, Chile
| | - Esteban Moraga-Escobar
- Programa de Neurociencia, Psiquiatría y Salud Mental, NEPSAM (http://nepsam.udec.cl), Universidad de Concepción, Barrio Universitario s/n, Casilla 160-C, Concepción 4070386, Chile; (B.V.); (K.S.); (E.M.-E.); (R.R.-P.); (X.M.)
| | - Romina Rojas-Ponce
- Programa de Neurociencia, Psiquiatría y Salud Mental, NEPSAM (http://nepsam.udec.cl), Universidad de Concepción, Barrio Universitario s/n, Casilla 160-C, Concepción 4070386, Chile; (B.V.); (K.S.); (E.M.-E.); (R.R.-P.); (X.M.)
- Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Barrio Universitario s/n, Box 160-C, Concepción 4070386, Chile;
| | - Paola Lagos
- Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Barrio Universitario s/n, Box 160-C, Concepción 4070386, Chile;
| | - Ximena Macaya
- Programa de Neurociencia, Psiquiatría y Salud Mental, NEPSAM (http://nepsam.udec.cl), Universidad de Concepción, Barrio Universitario s/n, Casilla 160-C, Concepción 4070386, Chile; (B.V.); (K.S.); (E.M.-E.); (R.R.-P.); (X.M.)
- Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Av. Juan Bosco s/n 3er Piso, Box 160-C, Concepción 4070529, Chile
| | - Juan-Luis Castillo-Navarrete
- Programa de Neurociencia, Psiquiatría y Salud Mental, NEPSAM (http://nepsam.udec.cl), Universidad de Concepción, Barrio Universitario s/n, Casilla 160-C, Concepción 4070386, Chile; (B.V.); (K.S.); (E.M.-E.); (R.R.-P.); (X.M.)
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Concepción, Barrio Universitario s/n, Box 160-C, Concepción 4070386, Chile
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Huang C, van Wijnen AJ, Im HJ. Serotonin Transporter (5-Hydroxytryptamine Transporter, SERT, SLC6A4) and Sodium-dependent Reuptake Inhibitors as Modulators of Pain Behaviors and Analgesic Responses. THE JOURNAL OF PAIN 2024; 25:618-631. [PMID: 37852405 PMCID: PMC11781314 DOI: 10.1016/j.jpain.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023]
Abstract
The serotonin transporter (5-hydroxytryptamine transporter [5-HTT], Serotonin Transporter (SERT), SLC6A4) modulates the activity of serotonin via sodium-dependent reuptake. Given the established importance of serotonin in the control of pain, 5-HTT has received much interest in studies of pain states and as a pharmacological target for serotonin reuptake inhibitors (SRIs). Animal models expressing varying levels of 5-HTT activity show marked differences in pain behaviors and analgesic responses, as well as many serotonin-related physiological effects. In humans, functional nucleotide variations in the SLC6A4 gene, which encodes the serotonin transporter 5-HTT, are associated with certain pathologic pain conditions and differences in responses to pharmacological therapy. These findings collectively reflect the importance of 5-HTT in the intricate physiology and management of pain, as well as the scientific and clinical challenges that need to be considered for the optimization of 5-HTT-related analgesic therapies. PERSPECTIVE: The serotonin transporter 5-HTT/SCL6A4 is sensitive to pharmacological SRIs. Experimental studies on the physiological functions of serotonin, as well as genetic mouse models and clinical phenotype/genotype correlations of nucleotide variation in the human 5-HTT/SCL6A4 gene, provide new insights for the use of SRIs in chronic pain management.
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Affiliation(s)
- Cary Huang
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois; Department of Anesthesiology, NewYork-Presbyterian/Weill Cornell Medical Center, New York, New York.
| | - Andre J van Wijnen
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois; Department of Biochemistry, University of Vermont, Burlington, Vermont.
| | - Hee-Jeong Im
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center (JBVAMC), Chicago, Illinois.
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Wannemüller A, Kumsta R, Moser D, Jöhren HP, Margraf J. DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment. J Psychiatr Res 2024; 170:73-80. [PMID: 38103452 DOI: 10.1016/j.jpsychires.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
Epigenetic alterations are regarded as a potential mechanism mediating the effects of environmental risk factors on vulnerability for a range of mental health problems. Recent studies have addressed the question whether DNA methylation patterns predict the outcome of psychological interventions and whether treatment effects might be associated with changes of DNA methylation. We assessed phobic fear symptoms, treatment-relevant traits and treatment response in 308 adults free of psychotropic medication - highly fearful of either spiders, blood-injury-injections, dental-treatments or heights - all subjected to highly standardized exposure-based one-session fear treatment. DNA methylation level of the promotor region of the serotonin transporter gene (SLC6A4) was assessed in either saliva samples (spider and dental treatment fear cohorts) or oral mucosa (BII, heights) to check whether possible effects are independent of the surrogate tissue examined. Moreover, in order to examine possible DNA methylation by genotype effects, patients were assessed for genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR). DNA methylation levels were neither associated with pre-treatment fear levels, treatment relevant traits or treatment outcome data even when allelic variation of the 5HTTLPR was considered. Overall DNA methylation levels were higher in saliva samples compared to buccal samples. In saliva samples there was a small pre- to post-treatment increase in DNA methylation, which, however, was also not associated with the investigated phenotypes. We conclude that DNA methylation of SLC6A4 is no suitable biomarker for response efficacy to highly standardized one-session exposure-based fear treatments.
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Affiliation(s)
- André Wannemüller
- Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Germany.
| | - Robert Kumsta
- Department of Genetic Psychology, Ruhr-Universität Bochum, Germany
| | - Dirk Moser
- Department of Genetic Psychology, Ruhr-Universität Bochum, Germany
| | | | - Jürgen Margraf
- Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Germany
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Gafarov VV, Gromova EA, Gubina MA, Gagulin IV, Maksimov VN, Gafarova AV. [The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression]. Zh Nevrol Psikhiatr Im S S Korsakova 2024; 124:135-139. [PMID: 38465822 DOI: 10.17116/jnevro2024124021135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
OBJECTIVE To study the relationship of polymorphic variants of the SLC6A4 gene with depression among people aged 25-44 years in Novosibirsk. MATERIAL AND METHODS Under the WHO program «MONICA-psychosocial (MOPSY)», a random representative sample of people aged 25-44 years from the population of the Oktyabrsky district of Novosibirsk (men n=725, mean age 43.4±0.4 years, response - 71.3%, women n=710, mean age 44.8±0.4 years, response - 72%). Depression was assessed using the MONICA-MOPSY psychosocial questionnaire. Every fourth respondent was examined for polymorphic variants of 5HTTLPR-VNTR SNP rs25531 A>G of the SLC6A4 gene. The study was carried out within the framework of the budget topic Reg. No. 122031700094-5. RESULTS The high level of depression among people aged 25-44 was 12.8% (for men 9.1%, for women - 15.92%); the average level of depression occurred in 24.5% of the population (among men in 21.24%, among women in 26.76%) (χ2=17.071, df=2, p<0.001). The most common genotype of the SLC6A4 gene, among people aged 25--4 years old in Novosibirsk, was SLA - 43.29%, LALA - 26.53% - in second place, SS - 17.87% - third, LALG - 6 genotypes were less represented genotypes. 74%, SLG - 4.18%, LGLG - 1.39%. Carrying the SLA genotype (53.3% and 63.6%) increased the chance of developing both the average level of depression by 2.359 (95% CI 1.278-4.355) times, and depression in general by 1.933 (95% CI 1.142-3.271) times, compared with persons carrying the LALA genotype (32.0% and 46.9%), (χ2=7.674, df=1, p<0.01 and χ2=6.095, df=1, p<0.05). Persons carrying the LALG genotype (54.5%) also had a higher chance of developing a mean level of depression RR=2.929 (95% CI 1.039-8.261), compared with carriers of the LALA genotype (32.0%) (χ2=4.326, df =1, p<0.05) (p<0.05). CONCLUSION Associative links between polymorphic variants of the SLC6A4 gene and depression have been established.
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Affiliation(s)
- V V Gafarov
- Research Institute of Therapy and Preventive Medicine - branch of the Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - E A Gromova
- Research Institute of Therapy and Preventive Medicine - branch of the Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - M A Gubina
- Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - I V Gagulin
- Research Institute of Therapy and Preventive Medicine - branch of the Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - V N Maksimov
- Research Institute of Therapy and Preventive Medicine - branch of the Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - A V Gafarova
- Research Institute of Therapy and Preventive Medicine - branch of the Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
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Zusman EZ, Chau CMY, Bone JN, Hookenson K, Brain U, Glier MB, Grunau RE, Weinberg J, Devlin AM, Oberlander TF. Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study. Dev Psychobiol 2023; 65:e22425. [PMID: 37860904 DOI: 10.1002/dev.22425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 10/21/2023]
Abstract
Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.
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Affiliation(s)
- Enav Z Zusman
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Cecil M Y Chau
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jeffrey N Bone
- Biostatistics, Clinical Research Support Unit, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Kaia Hookenson
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ursula Brain
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Melissa B Glier
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ruth E Grunau
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Joanne Weinberg
- Department of Cellular & Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Angela M Devlin
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tim F Oberlander
- BC Children's Hospital Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
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Castillo-Navarrete JL, Vicente B, Schmidt K, Moraga-Escobar E, Rojas-Ponce R, Lagos P, Macaya X, Guzman-Castillo A. Interaction of Val66Met BDNF and 5-HTTLPR polymorphisms with prevalence of post-earthquake 27-F PTSD in Chilean population. PeerJ 2023; 11:e15870. [PMID: 37692110 PMCID: PMC10484206 DOI: 10.7717/peerj.15870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 07/18/2023] [Indexed: 09/12/2023] Open
Abstract
Post-traumatic stress (PTSD) disorder is a mental health condition that can occur after experiencing or witnessing a traumatic event. The 27-F earthquake that struck Chile in 2010 was one such event that had a significant impact on the mental health of the population. A study was conducted to investigate the prevalence of PTSD and its associated factors among survivors of this earthquake. The study was a longitudinal design, involving a sample of 913 patients aged 18 to 75 years who attended 10 Primary Care Centers in Concepción, Chile. The Composite International Diagnostic Interview (CIDI) was used to assess both depressive episodes (DE) and PTSD before and after the earthquake. The study also involved genotyping studies using saliva samples from the participants, specifically focusing on the Val66Met and 5-HTTLPR polymorphisms. Statistical analysis was performed to examine the association between different variables and the presence of PTSD. These variables included demographic factors, family history of psychiatric disorders, DE, childhood maltreatment experiences, and critical traumatic events related to the earthquake. The results showed that the incidence of post-earthquake PTSD was 11.06%. No significant differences were found between the groups of participants who developed post-earthquake PTSD regarding the Val66Met or 5-HTTLPR polymorphisms. However, a significant association was found between the concomitant diagnosis of DE and the development of post-earthquake PTSD. The presence of DE doubled the risk of developing post-earthquake PTSD. The number of traumatic events experienced also had a statistically significant association with an increased risk of developing post-earthquake PTSD. The study's limitations include the potential interference of different DE subtypes, the complexity of quantifying the degree of earthquake exposure experienced by each individual, and events entailing social disruption, such as looting, that can profoundly influence distress. In conclusion, the study found that PTSD following the 27-F earthquake in Chile was associated with a concomitant diagnosis of DE and the number of traumatic events experienced. The study did not find a significant association between PTSD and the Val66Met or 5-HTTLPR polymorphisms. The researchers recommend that mental health professionals should prioritize the detection and treatment of concomitant depressive episodes and exposure to critical traumatic events in survivors of disasters. They also suggest that further research is needed to better understand the relationship between genetic factors and post-disaster PTSD.
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Affiliation(s)
- Juan-Luis Castillo-Navarrete
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
- Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
- Programa Doctorado Salud Mental, Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
| | - Benjamin Vicente
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
- Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
| | - Kristin Schmidt
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
- Programa Doctorado Salud Mental, Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
- Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
| | - Esteban Moraga-Escobar
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
| | - Romina Rojas-Ponce
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
- Programa Doctorado Salud Mental, Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
- Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Paola Lagos
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
- Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Ximena Macaya
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
- Facultad de Odontología, Universidad de Concepción, Concepción, Chile
| | - Alejandra Guzman-Castillo
- Programa Neurociencias, Psiquiatría y Salud Mental, NEPSAM, Universidad de Concepción, Concepción, Chile
- Programa Doctorado Salud Mental, Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
- Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción, Chile
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Støier JF, Jørgensen TN, Sparsø T, Rasmussen HB, Kumar V, Newman AH, Blakely RD, Werge T, Gether U, Herborg F. Disruptive mutations in the serotonin transporter associate serotonin dysfunction with treatment-resistant affective disorder. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.08.29.23294386. [PMID: 37693601 PMCID: PMC10491376 DOI: 10.1101/2023.08.29.23294386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Affective or mood disorders are a leading cause of disability worldwide. The serotonergic system has been heavily implicated in the complex etiology and serves as a therapeutic target. The serotonin transporter (SERT) is a major regulator of serotonin neurotransmission, yet the disease-relevance of impaired SERT function remains unknown. Here, we present the first identification and functional characterization of disruptive coding SERT variants found in patients with psychiatric diseases. In a unique cohort of 144 patients characterized by treatment-resistant chronic affective disorders with a lifetime history of electroconvulsive therapy, we identified two previously uncharacterized coding SERT variants: SERT-N217S and SERT-A500T. Both variants were significantly enriched in the patient cohort compared to GnomAD (SERT-N217S: OR = 151, P = 0.0001 and SERT-A500T: OR = 1348, P = 0.0022) and ethnicity-matched healthy controls (SERT-N217S: OR ≥ 17.7, P ≤ 0.013 and SERT-A500T: OR = ∞, P = 0.029). Functional investigations revealed that the mutations exert distinct perturbations to SERT function, but their overall effects converge on a partial loss-of-function molecular phenotype. Thus, the SERT-A500T variant compromises the catalytic activity, while SERT-N217S disrupts proper glycosylation of SERT with a resulting dominant-negative trafficking deficiency. Moreover, we demonstrate that the trafficking deficiency of SERT-N217S is amenable to pharmacochaperoning by noribogaine. Collectively, our findings describe the first disease-associated loss-of-function SERT variants and implicate serotonergic disturbances arising from SERT dysfunction as a risk factor for chronic affective disorders.
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Stoffel M, Rahn S, Neubauer AB, Moessner M, Aguilar-Raab C, Ditzen B. Associations of SLC6A4 methylation with salivary cortisol, salivary alpha-amylase, and subjective stress in everyday life. Psychoneuroendocrinology 2023; 153:106283. [PMID: 37196602 DOI: 10.1016/j.psyneuen.2023.106283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 03/31/2023] [Accepted: 04/27/2023] [Indexed: 05/19/2023]
Abstract
Dysregulations of the hypothalamic-pituitary-adrenal (HPA) and sympatho-adrenal medullary (SAM) axis are associated with mental and somatic illness. However, there is lack of knowledge regarding the molecular mechanisms underlying these effects. Epigenetic states in the serotonin transporter gene (SLC6A4) were shown to be associated with stress in various forms. We hypothesized that levels of DNA methylation (DNAm) of SLC6A4 would be associated with altered SAM- and HPA regulation in daily life. N = 74 healthy persons participated in the study. An ecological momentary assessment (EMA) approach was used to assess indicators of stress in daily life. Each day included six concurrent assessments of saliva, to quantify cortisol (sCort; HPA axis) and alpha-amylase (sAA; SAM axis), and to assess self-reports on subjective stress. To assess SLC6A4 DNAm, peripheral blood was drawn and analyzed via bisulfite pyrosequencing. All data were assessed in two waves three months apart, each including two days of EMA and the assessment of SLC6A4 DNAm. Data were analyzed using multilevel models. On the between-person level, higher average levels of SLC6A4 DNAm were associated with higher average levels of sAA, but not with average levels of sCort. On the within-person level, higher levels of SLC6A4 DNAm were associated with lower levels of sAA and sCort. There were no associations of subjective stress with SLC6A4 DNAm. The results help to clarify the association between environmental stress and stress axes regulation, pointing towards an important role of differential within- and between-person effects of SLC6A4 DNAm, which might shape this association.
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Affiliation(s)
- Martin Stoffel
- Institute of Medical Psychology, Center for Psychosocial Medicine, Heidelberg University Hospital, Ruprecht-Karls University Heidelberg, Bergheimer Straße 20, 69115 Heidelberg, Germany.
| | - Stefanie Rahn
- Clinic of Diagnostic and Interventional Radiology (DIR), Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Andreas B Neubauer
- Department for Education and Human Development, DIPF | Leibniz Institute for Research and Information in Education, Rostocker Straße 6, 60323 Frankfurt/Main, Germany
| | - Markus Moessner
- Center for Psychotherapy Research, Heidelberg University Hospital, Bergheimer Str. 54, 69115 Heidelberg, Germany
| | - Corina Aguilar-Raab
- Institute of Medical Psychology, Center for Psychosocial Medicine, Heidelberg University Hospital, Ruprecht-Karls University Heidelberg, Bergheimer Straße 20, 69115 Heidelberg, Germany
| | - Beate Ditzen
- Institute of Medical Psychology, Center for Psychosocial Medicine, Heidelberg University Hospital, Ruprecht-Karls University Heidelberg, Bergheimer Straße 20, 69115 Heidelberg, Germany.
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Zięba A, Matosiuk D, Kaczor AA. The Role of Genetics in the Development and Pharmacotherapy of Depression and Its Impact on Drug Discovery. Int J Mol Sci 2023; 24:2946. [PMID: 36769269 PMCID: PMC9917784 DOI: 10.3390/ijms24032946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023] Open
Abstract
Complex disorders, such as depression, remain a mystery for scientists. Although genetic factors are considered important for the prediction of one's vulnerability, it is hard to estimate the exact risk for a patient to develop depression, based only on one category of vulnerability criteria. Genetic factors also regulate drug metabolism, and when they are identified in a specific combination, may result in increased drug resistance. A proper understanding of the genetic basis of depression assists in the development of novel promising medications and effective disorder management schemes. This review aims to analyze the recent literature focusing on the correlation between specific genes and the occurrence of depression. Moreover, certain aspects targeting a high drug resistance identified among patients suffering from major depressive disorder were highlighted in this manuscript. An expected direction of future drug discovery campaigns was also discussed.
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Affiliation(s)
- Agata Zięba
- Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland
| | - Dariusz Matosiuk
- Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland
| | - Agnieszka A. Kaczor
- Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland
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10
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COMT but Not 5HTTLPR Gene Is Associated with Depression in First-Episode Psychosis: The Role of Stressful Life Events. Genes (Basel) 2023; 14:genes14020350. [PMID: 36833277 PMCID: PMC9956580 DOI: 10.3390/genes14020350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/10/2023] [Accepted: 01/26/2023] [Indexed: 02/03/2023] Open
Abstract
Serotonergic and dopaminergic systems are involved in the regulation of mood and reactivity to psychological stress. This study explores, in a sample of first episode psychosis (FEP) patients, whether more severe depressive symptoms were found in those who: (1) experienced a major stressful event in the 6 months preceding illness onset; and (2) were homozygous for the COMT Val158 allele or carrying the S allele of 5-HTTLPR. A total of 186 FEP patients recruited were assessed using the Hamilton Rating Scale for Depression (HAMD) for depressive symptoms. Stressful life events (SLEs) were collected by the List of Events Scale. The genotypes of 5-HTTLPR, rs25531, and COMT Val158 Met were performed. It has been found that higher levels of depression is associated with the presence of SLEs (p = 0.019) and with COMT Val158 allele homozygosity (p = 0.029), but not with carrying the S allele of 5-HTTLPR. The COMT gene moderates the association between depression and SLEs as Val158 allele homozygote patients experiencing SLEs had the highest level of depressive symptoms compared to the others (p = 0.002). The present study provides initial evidence for an effect of the COMT Val158 homozygosity and severe stressful life events on the severity of depressive symptoms in first episode psychosis.
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11
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Tour J, Sandström A, Kadetoff D, Schalling M, Kosek E. The OPRM1 gene and interactions with the 5-HT1a gene regulate conditioned pain modulation in fibromyalgia patients and healthy controls. PLoS One 2022; 17:e0277427. [PMID: 36342939 PMCID: PMC9639841 DOI: 10.1371/journal.pone.0277427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 10/27/2022] [Indexed: 11/09/2022] Open
Abstract
Fibromyalgia (FM) patients have dysfunctional endogenous pain modulation, where opioid and serotonergic signaling is implicated. The aim of this study was to investigate whether genetic variants in the genes coding for major structures in the opioid and serotonergic systems can affect pain modulation in FM patients and healthy controls (HC). Conditioned pain modulation (CPM), evaluating the effects of ischemic pain on pressure pain sensitivity, was performed in 82 FM patients and 43 HC. All subjects were genotyped for relevant functional polymorphisms in the genes coding for the μ-opioid receptor (OPRM1, rs1799971), the serotonin transporter (5-HTT, 5-HTTLPR/rs25531) and the serotonin 1a receptor (5-HT1a, rs6295). Results showed the OPRM1 G-allele was associated with decreased CPM. A significant gene-to-gene interaction was found between the OPRM1 and the 5-HT1a gene. Reduced CPM scores were seen particularly in individuals with the OPRM1 G*/5-HT1a CC genotype, indicating that the 5-HT1a CC genotype seems to have an inhibiting effect on CPM if an individual has the OPRM1 G-genotype. Thus, regardless of pain phenotype, the OPRM1 G-allele independently as well as with an interaction with the 5-HT1a gene influenced pain modulation. FM patients had lower CPM than HC but no group differences were found regarding the genetic effects on CPM, indicating that the results reflect more general mechanisms influencing pain modulatory processes rather than underlying the dysfunction of CPM in FM. In conclusion, a genetic variant known to alter the expression of, and binding to, the my-opioid receptor reduced a subject’s ability to activate descending pain inhibition. Also, the results suggest a genetically inferred gene-to-gene interaction between the main opioid receptor and a serotonergic structure essential for 5-HT transmission to modulate pain inhibition. The results in this study highlight the importance of studying joint synergistic and antagonistic effects of neurotransmittor systems in regard to pain modulation.
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Affiliation(s)
- Jeanette Tour
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology, Blekinge Hospital, Karlskrona, Sweden
- * E-mail:
| | - Angelica Sandström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Diana Kadetoff
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Stockholm Spine Center, Löwenströmska Hospital, Upplands Väsby, Sweden
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Eva Kosek
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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12
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No evidence for intervention-associated DNA methylation changes in monocytes of patients with posttraumatic stress disorder. Sci Rep 2022; 12:17347. [PMID: 36253434 PMCID: PMC9576776 DOI: 10.1038/s41598-022-22177-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/11/2022] [Indexed: 01/10/2023] Open
Abstract
DNA methylation patterns can be responsive to environmental influences. This observation has sparked interest in the potential for psychological interventions to influence epigenetic processes. Recent studies have observed correlations between DNA methylation changes and therapy outcome. However, most did not control for changes in cell composition. This study had two aims: first, we sought to replicate therapy-associated changes in DNA methylation of commonly assessed candidate genes in isolated monocytes from 60 female patients with post-traumatic stress disorder (PTSD). Our second, exploratory goal was to identify novel genomic regions with substantial pre-to-post intervention DNA methylation changes by performing whole-genome bisulfite sequencing (WGBS) in two patients with PTSD. Equivalence testing and Bayesian analyses provided evidence against physiologically meaningful intervention-associated DNA methylation changes in monocytes of PTSD patients in commonly investigated target genes (NR3C1, FKBP5, SLC6A4, OXTR). Furthermore, WGBS yielded only a limited set of candidate regions with suggestive evidence of differential DNA methylation pre- to post-therapy. These differential DNA methylation patterns did not prove replicable when investigated in the entire cohort. We conclude that there is no evidence for major, recurrent intervention-associated DNA methylation changes in the investigated genes in monocytes of patients with PTSD.
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13
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Zhang Y, Yao S, Schmitt H, Becker B, Kendrick KM, Montag C. Molecular genetic associations between a prominent serotonin transporter gene polymorphism (5-HTTLPR/rs25531) and individual differences in tendencies toward autistic traits and generalized internet use disorder in China and Germany. Brain Behav 2022; 12:e2747. [PMID: 36106519 PMCID: PMC9575603 DOI: 10.1002/brb3.2747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 07/18/2022] [Accepted: 08/03/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The serotonin transporter polymorphism 5-HTTLPR is an extensively investigated genetic marker of autistic traits or autism spectrum disorder, and recently has also been studied in the realm of internet use disorder (IUD), yet the findings remain controversial. Therefore, the present study aimed to explore associations between 5-HTTLPR (also including SNP rs25531) and autistic traits/IUD tendencies and to assess whether the relationship between autistic traits and IUD tendencies varies by this genetic marker in participants from China and Germany. METHODS A total of 540 Chinese and 563 German subjects were genotyped for 5-HTTLPR/rs25531 and completed the Adult Autism Spectrum Quotient questionnaire and the short version of the Internet Addiction Test. RESULTS Carriers of the low expressing S'S' genotype (S, LG ) showed significantly higher levels of autistic traits than the high expressing allele (e.g. LA ) carriers in both samples. There was no significant effect of 5-HTTLPR/rs25531 on IUD either in the Chinese or Germany samples, whereas positive correlations between autistic traits and IUD varied by 5-HTTLPR/rs25531 genotypes and also differed between Chinese and German samples. In the Chinese sample, positive correlations were mainly driven by S'S' and S'L' carriers, while they were mainly determined by S'L' and L'L' carriers in the German sample. Further analyses revealed that the associations between autistic traits and IUD tended in parts to be more strongly pronounced in the complete German sample compared to the complete Chinese sample, and also varied depending on 5-HTTLPR/rs25531 genotypes (in S'S' carriers: China > Germany; in S'L' and L'L' carriers: China < Germany; both in terms of more positive associations). CONCLUSIONS Our findings suggest carriers of low expressing alleles (S, LG ) are more likely to show higher autistic traits in both Chinese and German samples. Furthermore, the present work shows that both 5-HTTLPR/rs25531 and cultural differences might be of relevance to understand associations between autistic traits and IUD tendencies, but this needs to be further backed up.
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Affiliation(s)
- YingYing Zhang
- Department of Molecular Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany
| | - Shuxia Yao
- The Clinical Hospital of Chengdu Brain Science Institute, Ministry of Education Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Helena Schmitt
- Department of Molecular Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany
| | - Benjamin Becker
- The Clinical Hospital of Chengdu Brain Science Institute, Ministry of Education Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Keith M Kendrick
- The Clinical Hospital of Chengdu Brain Science Institute, Ministry of Education Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Christian Montag
- Department of Molecular Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany.,The Clinical Hospital of Chengdu Brain Science Institute, Ministry of Education Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
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14
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Genetic associations with resilience to potentially traumatic events and vantage sensitivity to social support. Arch Psychiatr Nurs 2022; 40:147-157. [PMID: 36064238 DOI: 10.1016/j.apnu.2022.07.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 05/30/2022] [Accepted: 07/03/2022] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Stress responses and mental health outcomes greatly vary when individuals are exposed to potentially traumatic events (PTEs). The Differential Susceptibility Model (DSM) (Pluess, 2015) suggests individual differences in stress responses are influenced by gene-environment interactions, with genes conferring reactivity. While individuals can be resilient (or vulnerable) to PTEs, they can also have vantage sensitivity (or resistance) to social support. This study examined whether selected genotypes moderated the effect of PTEs and social support on mental health. METHODS This cross-sectional candidate gene study included 450 college students (M age = 20.4, 79.3 % women) who provided buccal cells for genotyping and completed measures of psychosocial variables. DNA was genotyped for 12 genetic variants. RESULTS Hierarchical regression revealed that the Mental Health Inventory (MHI) was associated with the Trauma History Questionnaire (THQ), rs1800795 in IL-6, and THQ × rs1800795 [R2 = 0.10, F(3, 418) = 15.68, p < .01]. The MHI was associated with the Social Support Survey (SSS), rs4680 in COMT, and SSS × rs4680 [R2 = 0.24, F(3, 429) = 44.19, p < .01]. Only THQ and SSS survived multiple testing corrections. DISCUSSION Findings partially support the DSM that the G/G genotype of rs1800795 in IL-6 is associated with resilience to PTEs, and the Met/Met genotype of rs4680 in COMT is associated with vantage sensitivity to social support. Limitations include cross-sectional design, limited PTE measurement, small convenience sample, and noncorrection for multiple significance test. Clinicians need to view resilience holistically and understand resilience is associated with psychosocial and genetic factors.
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15
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Vrshek-Schallhorn S, Corneau GM, Grillo AR, Sapuram VR, Plieger T, Reuter M. Additive serotonergic genetic sensitivity and cortisol reactivity to lab-based social evaluative stress: Influence of severity across two samples. Psychoneuroendocrinology 2022; 142:105767. [PMID: 35525123 DOI: 10.1016/j.psyneuen.2022.105767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/28/2022] [Accepted: 04/10/2022] [Indexed: 11/29/2022]
Abstract
Prior work demonstrates that an additive serotonergic multilocus genetic profile score (MGPS) predicts amplified risk for depression following significant life stress, and that it interacts with elevations in the cortisol awakening response to predict depression. The serotonin system and HPA-axis have bidirectional influence, but whether this MGPS predicts acute cortisol reactivity, which might then serve as a mechanism for depression, is unknown. Our prior work suggests that depression risk factors predict blunted cortisol reactivity to explicit negative evaluative lab-based stress. Thus, we hypothesized that a 4-variant serotonergic MGPS (three SNPs from the original 5-variant version plus 5HTTLPR) would predict blunted cortisol reactivity to explicit negative evaluative stress versus a control. In Sample 1, growth curve modeling showed that the MGPS predicted heightened cortisol reactivity (p = 0.0001) in an explicitly negative evaluative Trier Social Stress Test variant (TSST) versus a control condition among non-depressed emerging adults (N = 152; 57% female). In Sample 2, 125 males completed the Socially Evaluative Cold Pressor Test (SECPT), an ambiguously negative evaluative manipulation; findings displayed a similar pattern but did not reach statistical significance (ps.075-.091). A participant-level meta-analysis of the two samples demonstrated a significant effect of negative evaluation severity, such that the MGPS effect size on reactivity increased linearly from control to SECPT to an explicitly negative evaluative TSST. Findings indicate that this MGPS contributes to sensitivity to social threat and that cortisol dysregulation in the context of social stress may be one mechanism by which this MGPS contributes to depression.
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Affiliation(s)
| | - Gail M Corneau
- Department of Psychology, University of North Carolina at Greensboro, USA
| | | | - Vaibhav R Sapuram
- Department of Psychology, University of North Carolina at Greensboro, USA
| | - Thomas Plieger
- Department of Psychology and Center for Economics & Neuroscience, Bonn University, Germany
| | - Martin Reuter
- Department of Psychology and Center for Economics & Neuroscience, Bonn University, Germany
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16
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Investigation of the Serotonergic Activity and the Serotonin Content in Serum and Platelet, and the Possible Role of the Serotonin Transporter in Patients with Depression. Behav Sci (Basel) 2022; 12:bs12060178. [PMID: 35735388 PMCID: PMC9220674 DOI: 10.3390/bs12060178] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/19/2022] [Accepted: 05/31/2022] [Indexed: 02/05/2023] Open
Abstract
According to the monoamine hypothesis, the development of depression is associated with dysfunctions of the serotonergic system. Alterations in the serotonin transporter gene (5-HTTLPR), the serotonergic activity in the brain, and the content of serotonin (5-HT) have been related to depression and were examined separately by previous studies. This study investigates these parameters in 89 depressed patients and 89 healthy participants. We investigated the serotonergic activity measured by the loudness dependence of auditory evoked potentials (LDAEP). In addition to the examination of the serotonin content (serum and platelet), enzyme-linked immunosorbent assays (ELISA) were used and 5-HTTLPR genotypes were analyzed. We observed a lower serotonin content in patients compared to healthy participants. Further, we noticed a correlation between anxiety and depression-associated symptoms with serotonergic activity. Patients treated with SSRI/SNRI showed decreased contents of serum serotonin compared to patients without any psychotropic medication or other psychotropic medications. Since the serotonergic activity, peripheral serotonin content, and 5-HTTLPR were unrelated, the results suggest independent alterations of central and peripheral serotonergic systems in depression. In line with this finding, serotonergic activity was related to anxiety and depression symptoms. Furthermore, the applied medication seems to influence serum serotonin content in patients with depression.
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17
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The Interaction between Serotonin Transporter Allelic Variation and Maternal Care Modulates Instagram Sociability in a Sample of Singaporean Users. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19095348. [PMID: 35564743 PMCID: PMC9105050 DOI: 10.3390/ijerph19095348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/12/2022] [Accepted: 04/24/2022] [Indexed: 02/01/2023]
Abstract
Human social interactions ensure recognition and approval from others, both in offline and online environments. This study applies a model from behavioral genetics on Instagram sociability to explore the impact of individual development on behavior on social networks. We hypothesize that sociable attitudes on Instagram resulted from an interaction between serotonin transporter gene alleles and the individual’s social relationship with caregivers. We assess the environmental and genetic components of 57 Instagram users. The self-report questionnaire Parental Bonding Instrument is adopted to determine the quality of parental bonding. The number of posts, followed users (“followings”), and followers are collected from Instagram as measures of online social activity. Additionally, the ratio between the number of followers and followings (“Social Desirability Index”) was calculated to estimate the asymmetry of each user’s social network. Finally, buccal mucosa cell samples were acquired, and the polymorphism rs25531 (T/T homozygotes vs. C-carriers) within the serotonin transporter gene was examined. In the preliminary analysis, we identified a gender effect on the number of followings. In addition, we specifically found a gene–environment interaction on the standardized Instagram “Social Desirability Index” in line with our predictions. Users with the genotype more sensitive to environmental influences (T/T homozygotes) showed a higher Instagram “Social Desirability Index” than nonsensitive ones (C-carriers) when they experienced positive maternal care. This result may contribute to understanding online social behavior from a gene*environment perspective.
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18
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Sangüesa E, Cirujeda C, Concha J, Padilla PP, García CB, Ribate MP. Exploring the usefulness of plasma level determination and pharmacogenetics for patients treated with clozapine. Per Med 2022; 19:181-192. [PMID: 35259926 DOI: 10.2217/pme-2021-0029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Aims: The aims of the present study were to assess the variance of plasma clozapine (CLZ) levels and to identify the influence of sociodemographic and pharmacogenetic factors on it and to introduce these tools in a clinical setting. Patients & methods: CLZ concentration was measured and genetic variants of CLZ pharmacokinetic and pharmacodynamic factors were assessed in 23 patients with psychotic disorders. Results: A significant association between mean concentration/dose ratio (C/D) and smoking status, age and weight were found. There was a significant difference in mean plasma CLZ levels and gender. The rs762551 AA genotype in smokers had a significantly lower C/D. Conclusion: In addition to classical factors, monitoring of plasma concentrations together with pharmacogenetics led to greater individualization of treatment.
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Affiliation(s)
- Estela Sangüesa
- Pharmacy degree, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain
| | - Christine Cirujeda
- Centro Neuropsiquiátrico Nuestra Señora del Carmen. Hermanas Hospitalarias, Zaragoza, Spain
| | - Julia Concha
- Pharmacy degree, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain
| | - Pedro Pablo Padilla
- Centro Neuropsiquiátrico Nuestra Señora del Carmen. Hermanas Hospitalarias, Zaragoza, Spain
| | - Cristina Belén García
- Pharmacy degree, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain
| | - María Pilar Ribate
- Pharmacy degree, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain
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19
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Ollmann TM, Seidl E, Venz J, Pieper L, Voss C, Hoyer J, Kische H, Poppenhäger SR, Schiele MA, Domschke K, Beesdo-Baum K. 5-HTT genotype and inertia of negative affect in adolescents and young adults from the general population. J Neural Transm (Vienna) 2022; 129:343-351. [PMID: 35246765 PMCID: PMC8930868 DOI: 10.1007/s00702-022-02459-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 01/03/2022] [Indexed: 11/28/2022]
Abstract
The study aims to replicate the previous found association of 5-HTTLPR and inertia of negative affect in daily life of adolescents and young adults. Data of 877 adolescents (aged 14–21 years) of the Behavior and Mind Health (BeMIND) study (epidemiological cohort study, Dresden, Germany) were genotyped for 5-HTTLPR/rs25531, grouped into SS/SLG/SLA/LGLA/LGLG vs. LALA, and provided ratings on negative affect items, depression and anxiety (Patient-Reported Outcomes Measurement Information System) eight times a day over 4 days. Multilevel regression models did not reveal an association of 5-HTTLPR genotype and inertia of negative affect, nor associations with inertia of anxiety or depression. Inertia of negative affect seems not to be a psychological mechanism through which 5-HTTLPR acts on psychopathology.
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Affiliation(s)
- T. M. Ollmann
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
| | - E. Seidl
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
| | - J. Venz
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
- Center for Clinical Epidemiology and Longitudinal Studies (CELOS), Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - L. Pieper
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
- Center for Clinical Epidemiology and Longitudinal Studies (CELOS), Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - C. Voss
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
| | - J. Hoyer
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
| | - H. Kische
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
| | - S. R. Poppenhäger
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
| | - M. A. Schiele
- Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - K. Domschke
- Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Basics in NeuroModulation, Medical Faculty, University of Freiburg, Freiburg, Germany
| | - K. Beesdo-Baum
- Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
- Center for Clinical Epidemiology and Longitudinal Studies (CELOS), Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
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20
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Tanahashi S, Tanii H, Konishi Y, Otowa T, Sasaki T, Tochigi M, Okazaki Y, Kaiya H, Okada M. Association of Serotonin Transporter Gene (5-HTTLPR/rs25531) Polymorphism with Comorbidities of Panic Disorder. Neuropsychobiology 2022; 80:333-341. [PMID: 33333511 DOI: 10.1159/000512699] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/27/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Panic disorder (PD) has many comorbidities such as depression, bipolar disorder (BPD), and agoraphobia (AG). PD is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Recently, a tri-allelic serotonin transporter (5-HTTLPR/rs25531) polymorphism was reported to be more sensitive to personality traits compared to the bi-allelic 5-HTTLPR polymorphism. We hypothesized that the 5-HTTLPR/rs25531 polymorphism may lead to a pathological anxious state depending on the presence or absence of a comorbidity in PD. METHODS In this study, we investigated the relationship between comorbidities in PD and tri-allelic 5-HTTLPR polymorphisms. A total of 515 patients with PD (148 males, 367 females) were genotyped, and the Revised NEO Personality Inventory as well as anxiety-related psychological tests were administered. Depression, BPD, and AG were diagnosed as comorbidities. RESULTS For the tri-allele 5-HTTLPR genotype, a significant interaction effect was found between openness to experience and comorbid depression. Examination of the interaction between AG and the tri-allelic 5-HTTLPR genotype revealed that L' allele carriers are associated with higher trait anxiety than the S'S' genotype group in PD without AG. CONCLUSION Some anxiety and personality traits can be characterized by the tri-allelic gene effect of 5-HTTLPR. These results suggest that tri-allelic 5-HTTLPR genotypes have genetic effects on the presence of comorbidities of PD.
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Affiliation(s)
- Shunsuke Tanahashi
- Division of Neuroscience, Department of Psychiatry, Graduate School of Medicine, Brain Science and Animal Model Research Center, Mie University, Tsu, Japan
| | - Hisashi Tanii
- Division of Neuroscience, Department of Psychiatry, Graduate School of Medicine, Brain Science and Animal Model Research Center, Mie University, Tsu, Japan, .,Center for Physical and Mental Health, Mie University, Tsu, Japan,
| | - Yoshiaki Konishi
- Division of Neuroscience, Department of Psychiatry, Graduate School of Medicine, Brain Science and Animal Model Research Center, Mie University, Tsu, Japan
| | - Takeshi Otowa
- Department of Neuropsychiatry, NTT Medical Center Tokyo, Tokyo, Japan
| | - Tsukasa Sasaki
- Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan
| | - Mamoru Tochigi
- Department of Psychiatry, Teikyo University School of Medicine, Tokyo, Japan
| | - Yuji Okazaki
- Department of Psychiatry, Koseikai Michinoo Hospital, Nagasaki, Japan
| | - Hisanobu Kaiya
- Panic Disorder Research Center, Warakukai Medical Corporation, Tokyo, Japan
| | - Motohiro Okada
- Division of Neuroscience, Department of Psychiatry, Graduate School of Medicine, Brain Science and Animal Model Research Center, Mie University, Tsu, Japan
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21
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Sudden infant death syndrome revisited: serotonin transporter gene, polymorphisms and promoter methylation. Pediatr Res 2022; 92:694-699. [PMID: 34764460 PMCID: PMC9556327 DOI: 10.1038/s41390-021-01773-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/17/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Based on findings in the brain stems of SIDS victims, the serotonin transporter (5-HTT) gene has been discussed to be associated with SIDS. METHODS In the largest study to date, we investigated the promoter length (5-HTTLPR) and intron 2 VNTR polymorphisms in 274 cases and 264 controls and the Ile425Val polymorphism in 65 cases and 64 controls. Moreover, the methylation of the internal promoter region was investigated in 35 cases and 14 controls. RESULTS For 5-HTTLPR, we observed a trend towards an association of allele L (58.8% vs. 53.4%) with SIDS and significant results were observed after stratifying for age, season at death, and prone position. Nevertheless, when pooling all published data, a significant association of allele L with SIDS is confirmed (p: 0.001). For the intron 2 VNTR polymorphism, no significant differences were observed. After pooling, a significant accumulation of the rare allele 9 was observed in SIDS (2.1% vs. 0.6%; p: 0.018). For the Ile425Val polymorphism, no differences were observed. CONCLUSION We conclude that genetic variation at this gene might be of some importance in SIDS. Epigenetic analysis of the internal promoter, however, revealed no influence on the relative risk to succumb to SIDS. IMPACT This is the largest study published up to now on 5-HTT gene polymorphisms and SIDS. Polymorphisms in the 5-HTT gene appear to contribute (although to a small degree) to the risk to die from SIDS. There is no evidence that a methylation of the promoter region is of impact for the etiology of SIDS.
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22
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Hollerbach P, Olderbak S, Wilhelm O, Montag C, Jung S, Neumann CS, Habermeyer E, Mokros A. Associations of the MAOA uVNTR genotype and 5-HTTLPR/rs25531 haplotype with psychopathic traits. Psychoneuroendocrinology 2021; 131:105275. [PMID: 34102427 DOI: 10.1016/j.psyneuen.2021.105275] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/30/2021] [Accepted: 05/13/2021] [Indexed: 12/26/2022]
Abstract
Previous studies have linked polymorphisms of the monoamine oxidase A (MAOA uVNTR) and serotonin transporter gene (5-HTTLPR) to individual differences in the expression of psychopathic traits, but findings remain inconsistent. One possible reason is that these studies have treated psychopathy as a unitary construct when there is accumulating evidence that there are variants or subtypes. We used a variable-centered and a person-centered approach by (a) examining putative genetic correlates of psychopathy across individuals and (b) comparing the frequencies of the MAOA uVNTR genotype and 5-HTTLPR/rs25531 haplotype between empirically derived subtypes of psychopathy, respectively. Notably, we included the often neglected rs25531 polymorphism, which is closely connected to the 5-HTTLPR. Based on data from male offenders and community volunteers, structural equation modeling indicated that the 5-HTTLPR/rs25531 haplotype was specifically associated with interpersonal deficits beyond the overarching psychopathy construct. Latent profile analysis revealed four clusters that were labeled non-psychopaths, sociopaths, callous-conning, and psychopaths. The low-activity variant of the 5-HTTLPR/rs25531 haplotype was significantly more frequent in the callous-conning compared to the non-psychopathic subtype. There were no effects for the MAOA uVNTR. The results illustrate that psychopathy should not be treated as a unitary construct but that there are variants with specific profiles of psychopathic traits, and that the 5-HTTLPR/rs25531 haplotype plays a role in the manifestation of interpersonal deficits from a variable-centered as well as from a person-centered view.
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Affiliation(s)
- Pia Hollerbach
- Institute for Sex Research, Sexual Medicine & Forensic Psychiatry, Center for Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Forensic Psychiatry, University Hospital of Psychiatry Zurich, Zurich, Switzerland.
| | - Sally Olderbak
- Ulm University, Institute of Psychology and Education, Ulm, Germany.
| | - Oliver Wilhelm
- Ulm University, Institute of Psychology and Education, Ulm, Germany.
| | - Christian Montag
- Ulm University, Institute of Psychology and Education, Ulm, Germany; The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, School of Life Science and Technology, Chengdu, China.
| | - Sonja Jung
- Ulm University, Institute of Psychology and Education, Ulm, Germany.
| | - Craig S Neumann
- Department of Psychology, University of North Texas, Denton, TX, USA.
| | - Elmar Habermeyer
- Department of Forensic Psychiatry, University Hospital of Psychiatry Zurich, Zurich, Switzerland.
| | - Andreas Mokros
- Department of Psychology, FernUniversität in Hagen (University of Hagen), Hagen, Germany.
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23
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Ohtsubo Y, Matsunaga M, Masuda T, Noguchi Y, Yamasue H, Ishii K. Test of the Serotonin Transporter Gene × Early Life Stress Interaction Effect on Subjective Well‐Being and Loneliness Among Japanese Young Adults. JAPANESE PSYCHOLOGICAL RESEARCH 2021. [DOI: 10.1111/jpr.12376] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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24
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Huang Y, Gao J, Gao P, Peng D, Dai Y, Jiang H, Zhang X. A comprehensive assessment of genetic variation in serotonin transporter gene (5-HTTLPR+rs25531) and the response to dapoxetine in Chinese patients with premature ejaculation. Andrologia 2021; 53:e14141. [PMID: 34118072 DOI: 10.1111/and.14141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/13/2021] [Accepted: 05/21/2021] [Indexed: 11/29/2022] Open
Abstract
This study was to explore whether serotonin transporter gene-linked polymorphic region polymorphisms (5-HTTLPR+rs25531) influence the response to dapoxetine treatment in a Chinese population with premature ejaculation (PE). 112 patients with PE re-enrolled from our previous study received dapoxetine monotherapy. At the endpoint, patients with S'S' had a significant increased risk of nonresponse compared with L' carriers (p < .001). The improvement in S'S' genotype was significantly lower in premature ejaculation profile (PEP) items of 'control over ejaculation' (p = .035) and 'distress related to ejaculation' (p = .017) than that in L' carriers. As to clinical global impression of change (CGIC), results in S'S' subjects showed significantly lower scores (p = .008) and a less satisfaction rate reporting at least 'better' (p = .020) compared with L' carriers. Moreover, our findings suggested that patients with S'S' were more likely to develop adverse effects (AEs) compared with L' carriers (p = .040). This study suggests that PE patients bearing the S'S' genotype have an inferior comprehensive efficacy and safety of dapoxetine treatment, which consist of poorer response in IELTs, less improvement in patient-reported outcome (PRO) measures and greater incidence of AEs, than L' carriers. Variants of triallelic 5-HTTLPR may play a major role as a predictor of treatment response to dapoxetine.
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Affiliation(s)
- Yuanyuan Huang
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jingjing Gao
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Pan Gao
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dangwei Peng
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yutian Dai
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Hui Jiang
- Department of Andrology, Peking University Third Hospital, Beijing, China.,Department of Human Sperm Bank, Peking University Third Hospital, Beijing, China
| | - Xiansheng Zhang
- Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, China
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25
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Ellerbrock I, Sandström A, Tour J, Fanton S, Kadetoff D, Schalling M, Jensen KB, Sitnikov R, Kosek E. Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls. Mol Brain 2021; 14:81. [PMID: 33980291 PMCID: PMC8117625 DOI: 10.1186/s13041-021-00789-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/05/2021] [Indexed: 11/24/2022] Open
Abstract
The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5‐HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5‐HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5‐HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5‐HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5‐HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.
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Affiliation(s)
- Isabel Ellerbrock
- Department of Clinical Neuroscience, Karolinska Insitutet, Nobels väg 9, 17177, Stockholm, Sweden. .,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
| | - Angelica Sandström
- Department of Clinical Neuroscience, Karolinska Insitutet, Nobels väg 9, 17177, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Jeanette Tour
- Department of Clinical Neuroscience, Karolinska Insitutet, Nobels väg 9, 17177, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.,Department of Oncology, Blekinge Hospital, Karlskrona, Sweden
| | - Silvia Fanton
- Department of Clinical Neuroscience, Karolinska Insitutet, Nobels väg 9, 17177, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Diana Kadetoff
- Department of Clinical Neuroscience, Karolinska Insitutet, Nobels väg 9, 17177, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.,Stockholm Spine Center, Löwenströmska Hospital, Upplands Väsby, Sweden
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Karin B Jensen
- Department of Clinical Neuroscience, Karolinska Insitutet, Nobels väg 9, 17177, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Rouslan Sitnikov
- MRI Research Center, Karolinska University Hospital, Stockholm, Sweden
| | - Eva Kosek
- Department of Clinical Neuroscience, Karolinska Insitutet, Nobels väg 9, 17177, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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26
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Hande SH, Krishna SM, Sahote KK, Dev N, Erl TP, Ramakrishna K, Ravidhran R, Das R. Population genetic variation of SLC6A4 gene, associated with neurophysiological development. J Genet 2021. [DOI: 10.1007/s12041-021-01266-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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27
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The neurobiology of human aggressive behavior: Neuroimaging, genetic, and neurochemical aspects. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106:110059. [PMID: 32822763 DOI: 10.1016/j.pnpbp.2020.110059] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 06/12/2020] [Accepted: 08/03/2020] [Indexed: 12/18/2022]
Abstract
In modern societies, there is a strive to improve the quality of life related to risk of crimes which inevitably requires a better understanding of brain determinants and mediators of aggression. Neurobiology provides powerful tools to achieve this end. Pre-clinical and clinical studies show that changes in regional volumes, metabolism-function and connectivity within specific neural networks are related to aggression. Subregions of prefrontal cortex, insula, amygdala, basal ganglia and hippocampus play a major role within these circuits and have been consistently implicated in biology of aggression. Genetic variations in proteins regulating the synthesis, degradation, and transport of serotonin and dopamine as well as their signal transduction have been found to mediate behavioral variability observed in aggression. Gene-gene and gene-environment interactions represent additional important risk factors for aggressiveness. Considering the social burden of pathological forms of aggression, more basic and translational studies should be conducted to accelerate applications to clinical practice, justice courts, and policy making.
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28
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Schiele MA, Reif A, Lin J, Alpers GW, Andersson E, Andersson G, Arolt V, Bergström J, Carlbring P, Eley TC, Esquivel G, Furmark T, Gerlach AL, Hamm A, Helbig-Lang S, Hudson JL, Lang T, Lester KJ, Lindefors N, Lonsdorf TB, Pauli P, Richter J, Rief W, Roberts S, Rück C, Schruers KRJ, Thiel C, Wittchen HU, Domschke K, Weber H, Lueken U. Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis. Eur Neuropsychopharmacol 2021; 44:105-120. [PMID: 33483252 DOI: 10.1016/j.euroneuro.2021.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/12/2020] [Accepted: 01/10/2021] [Indexed: 12/25/2022]
Abstract
There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.
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Affiliation(s)
- Miriam A Schiele
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Jiaxi Lin
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Georg W Alpers
- Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany
| | - Evelyn Andersson
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Gerhard Andersson
- Department of Behavioural Sciences and Learning, Division of Psychology, Linköping University, Linköping, Sweden
| | - Volker Arolt
- Institute of Translational Psychiatry, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - Jan Bergström
- Department of Psychology, Stockholm University, Stockholm, Sweden
| | - Per Carlbring
- Department of Psychology, Stockholm University, Stockholm, Sweden
| | - Thalia C Eley
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, United Kingdom
| | - Gabriel Esquivel
- School for Mental Health and Neuroscience, Maastricht University, The Netherlands and Mondriaan Mental Health Center, Maastricht, The Netherlands
| | - Tomas Furmark
- Department of Psychology, Uppsala University, Uppsala, Sweden
| | - Alexander L Gerlach
- Department of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany
| | - Alfons Hamm
- Department of Psychology, University of Greifswald, Greifswald, Germany
| | - Sylvia Helbig-Lang
- Department of Clinical Psychology and Psychotherapy, University of Hamburg, Hamburg, Germany
| | - Jennifer L Hudson
- Department of Psychology, Centre for Emotional Health, Macquarie University, Sydney, NSW, Australia
| | - Thomas Lang
- Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany; Department of Psychology and Methods, Jacobs University Bremen, Germany
| | - Kathryn J Lester
- School of Psychology, University of Sussex, Brighton, United Kingdom
| | - Nils Lindefors
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Sweden
| | - Tina B Lonsdorf
- Institute for Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Paul Pauli
- Department of Psychology (Biological Psychology, Clinical Psychology, and Psychotherapy), and Center of Mental Health, Julius-Maximilians-Universität Würzburg, Würzburg, Germany
| | - Jan Richter
- Department of Psychology, University of Greifswald, Greifswald, Germany
| | - Winfried Rief
- Division of Clinical Psychology and Psychotherapy, Department of Psychology, Philipps University Marburg, Marburg, Germany
| | - Susanna Roberts
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, United Kingdom
| | - Christian Rück
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Sweden
| | - Koen R J Schruers
- School for Mental Health and Neuroscience, Maastricht University, The Netherlands and Mondriaan Mental Health Center, Maastricht, The Netherlands
| | - Christiane Thiel
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Hans-Ulrich Wittchen
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Germany
| | - Heike Weber
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany; Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany
| | - Ulrike Lueken
- Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
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29
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Ollmann TM, Voss C, Venz J, Seidl E, Hoyer J, Kische H, Pieper L, Schiele MA, Domschke K, Beesdo-Baum K. The interaction of 5-HTT variation, recent stress, and resilience on current anxiety levels in adolescents and young adults from the general population. Depress Anxiety 2021; 38:318-327. [PMID: 33058370 DOI: 10.1002/da.23101] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 08/11/2020] [Accepted: 09/09/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Previous work on gene-environment (GxE) interplay concerning anxiety has focused on the interaction of 5-HTTLPR with childhood adversities or traumatic events whereas the impact of recent stressors is understudied, as is the integration of resilience. The current study aimed to investigate the interactive effect of 5-HTTLPR and recent stress on anxiety in adolescents considering resilience as buffer of a GxE risk constellation. METHOD In a random population-based sample of 14-21 years old from Dresden, Germany, (N = 1180; genotyped = 942) recent stress (Daily Hassles [DH] Scale, Perceived Stress Scale, Screening Scale of the Trier Inventory for the Assessment of Chronic Stress), resilience (Connor-Davidson resilience scale) and anxiety (Patient Reported Outcome Measurement Information System Anxiety Short Form) were assessed via questionnaire in 2015 or 2016. RESULTS Fractional regression models revealed that resilience interacted with recent stress in form of DH as well as recent chronic stress and 5-HTTLPR regarding anxiety. Participants carrying the more active LA LA genotype reported consistently higher levels of anxiety when experiencing more DH or more recent chronic stress and having low levels of resilience. When the resilience scores were high, LA LA carriers reported the lowest anxiety scores despite DH or recent chronic stress. CONCLUSION Findings revealed an interactive relationship between 5-HTTLPR genotype and recent stress suggesting resilience to function as an additional dimension buffering the impact of a GxE risk constellation. Early interventions to build resilience may be useful to prevent an escalation of distress and associated unfavorable health outcomes.
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Affiliation(s)
- Theresa M Ollmann
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - Catharina Voss
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - John Venz
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.,Institute of Clinical Psychology and Psychotherapy, Center for Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Dresden, Germany
| | - Esther Seidl
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - Jana Hoyer
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - Hanna Kische
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - Lars Pieper
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.,Institute of Clinical Psychology and Psychotherapy, Center for Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Dresden, Germany
| | - Miriam A Schiele
- Department of Psychiatry and Psychotherapy, University of Freiburg, Freiburg, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, Center for Basics in NeuroModulation, University of Freiburg, Freiburg, Germany
| | - Katja Beesdo-Baum
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.,Institute of Clinical Psychology and Psychotherapy, Center for Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Dresden, Germany
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30
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The effects of 5-HTTLPR/rs25531 serotonin transporter gene polymorphisms on antisocial personality disorder among criminals in a sample of the Turkish population. Mol Biol Rep 2021; 48:77-84. [PMID: 33452587 DOI: 10.1007/s11033-021-06137-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/02/2021] [Indexed: 10/22/2022]
Abstract
Antisocial personality disorder (ASPD) is a cluster B personality disorder characterized by a disposition for criminal behaviors. It has been determined by previous studies that ASPD may have a genetic origin and the human serotonin transporter gene (SLC6A4) is one of the two serotonergic genes expected to be associated with this disorder. 5-HTT-linked polymorphic promoter region (5-HTTLPR) is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter. Among many polymorphisms in SLC6A4, 5-HTTLPR an insertion/deletion (indel) polymorphism and rs25531 single nucleotide polymorphism (SNP) in the 5-HTTLPR polymorphic region contribute to the regulation of SLC6A4 expression. In this study, we aimed to reveal the relationship between frequencies of 5-HTTLPR variants and ASPD among criminals in the Turkish population. Moreover, it was also attempted to figure out the SLC6A4 gene expression level differences regarding these polymorphisms. The 5-HTTLPR/rs25531 genotypes were determined by PCR and restriction length polymorphism (RFLP) analyses and quantitative real-time-PCR was done for measuring the gene expression levels in the case and control groups. Although no significant difference was observed in the distributions of the 5-HTTLPR/rs25531 polymorphisms between the case and control groups, SLC6A4 expression level in the control group was found significantly higher than the case group (p < 0.0001). There was also no significant difference between genotypes in terms of mRNA expression levels in either the control or the case group. According to our results, ASPD in Turkish society is associated with the SLC6A4 gene expression levels, though the distributions of 5-HTTLPR polymorphisms are not different. This study sheds light on future relevant studies as the first study which is conducted in criminals with ASPD in the Turkish community.
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31
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Beversdorf DQ, Shah A, Jhin A, Noel-MacDonnell J, Hecht P, Ferguson BJ, Bruce D, Tilley M, Talebizadeh Z. microRNAs and Gene-Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the SERT Gene on Maternal microRNA Expression. Front Psychiatry 2021; 12:668577. [PMID: 34290629 PMCID: PMC8288023 DOI: 10.3389/fpsyt.2021.668577] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter (SERT) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting. Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low). Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies. Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.
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Affiliation(s)
- David Q Beversdorf
- Departments of Radiology, Neurology, and Psychological Sciences, William and Nancy Thompson Endowed Chair in Radiology, University of Missouri, Columbia, MO, United States.,Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, United States
| | - Ayten Shah
- Children's Mercy Hospital, Kansas City, MO, United States
| | - Allison Jhin
- Kansas City University, Kansas City, MO, United States
| | - Janelle Noel-MacDonnell
- Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
| | - Patrick Hecht
- Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, United States
| | - Bradley J Ferguson
- Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, United States.,Health Psychology, Radiology, and Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, MO, United States
| | - Danielle Bruce
- Department of Biology, Central Methodist University, Fayette, MO, United States
| | - Michael Tilley
- Department of Biology, Central Methodist University, Fayette, MO, United States
| | - Zohreh Talebizadeh
- Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
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32
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Warnke K, Brandt J, Jörgens S, Arolt V, Beer K, Domschke K, Haverkamp W, Kuhlmann SL, Müller-Nordhorn J, Rieckmann N, Schwarte K, Ströhle A, Tschorn M, Waltenberger J, Grosse L. Association of 5-HTTLPR/rs25531 with depressive symptoms in patients with coronary heart disease: A prospective study. J Affect Disord 2020; 277:531-539. [PMID: 32889377 DOI: 10.1016/j.jad.2020.08.046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 06/06/2020] [Accepted: 08/20/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND 5-HTTLPR/rs25531 is suspected to be involved in the pathogenesis of both coronary heart disease (CHD)1 and depression. We aimed to investigate the role of 5-HTTLPR/rs25531 in the development of depressive symptoms among CHD patients in a longitudinal design. METHODS N = 265 participants with CHD diagnosis were included while hospitalized in a department of cardiology and genotyped for the 5-HTTLPR/rs25531. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9)7 at baseline and after 6 and 12 months. Binary logistic regression models were used to analyze the association of 5-HTTLPR/rs25531 with the prevalence of depressive symptoms at each time point as well as with the incidence and persistence of depressive symptoms at follow-up. RESULTS "LALA" genotype was associated with a higher prevalence of depressive symptoms 12 months after study inclusion. "LALA" genotype was associated with a higher incidence of depressive symptoms 6 and 12 months after study inclusion. There was no association of 5-HTTLPR/rs25531 with the persistence of depressive symptoms. LIMITATIONS Inclusion criteria did not demand a particular cardiac event at baseline, which aggravated the interpretation of the time-specific results. The majority of the participants was of male gender which could cause bias. The present study only vaguely differentiated between ethnical groups which might cause bias regarding nationality-dependent allele distributions. CONCLUSION The present study suggests a time-dependent association of the "LALA" genotype with depressive symptoms in CHD patients. 5-HTTLPR/rs25531 might be an important marker to detect risk groups for later onset depressive symptoms among CHD patients.
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Affiliation(s)
- Katharina Warnke
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Germany.
| | - Julia Brandt
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Germany
| | - Silke Jörgens
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Germany
| | - Volker Arolt
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Germany
| | - Katja Beer
- Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Wilhelm Haverkamp
- Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Internal Medicine and Cardiology, Berlin, Germany
| | - Stella L Kuhlmann
- Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Division of Emergency and Acute Medicine (CVK, CCM), Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Institute of Public Health, Berlin, Germany
| | - Jacqueline Müller-Nordhorn
- Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Institute of Public Health, Berlin, Germany; Bavarian Food and Health Safety Authority, Oberschleißheim, Germany
| | - Nina Rieckmann
- Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Institute of Public Health, Berlin, Germany
| | - Kathrin Schwarte
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Germany
| | - Andreas Ströhle
- Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany
| | - Mira Tschorn
- Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany; Social and Preventive Medicine, University of Potsdam, Potsdam, Germany
| | | | - Laura Grosse
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Germany; Intercultural Business Psychology, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany
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Wannemueller A, Forkmann T, Glaesmer H, Juckel G, Paashaus L, Rath D, Schönfelder A, Moser D, Kumsta R, Teismann T. The role of the 5-HTTLPR polymorphism in acquired capability for suicide. Suicide Life Threat Behav 2020; 50:1121-1126. [PMID: 32706152 DOI: 10.1111/sltb.12660] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/10/2020] [Accepted: 03/23/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE According to the Interpersonal Psychological Theory of Suicide, capability for suicide comprises two dimensions: fearlessness about death and elevated pain tolerance. The short (S) allelic variant of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) has repeatedly been associated with more violent and lethal suicide methods and lethality of suicide attempts. The current study aimed to investigate whether 5-HTTLPR allelic variants are associated with fearlessness about death and pain tolerance/persistence and whether it moderates the relationship between childhood maltreatment and acquired capability for suicide. METHOD A cohort of 208 inpatients hospitalized due to a recent suicide attempt or severe suicidal ideation was genotyped for the 5-HTTLPR and assessed for childhood maltreatment. Subjective pain tolerance and fearlessness about death as well as objective pain persistence was assessed using a pressure algometer. RESULTS Fearlessness about death, pain tolerance, and pain persistence did not differ between 5-HTTLPR genotypes. However, there was a significant correlation between self-reported childhood maltreatment and fearlessness about death that emerged exclusively in homozygous S-allele carriers. CONCLUSION Results suggest that there are no "high-risk"-alleles that generally increase capability for suicide. However, in terms of future suicide-related behaviors exposure to childhood maltreatment events could exert a particularly negative influence on homozygous S-allele carriers by increasing their fearlessness about death.
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Affiliation(s)
- Andre Wannemueller
- Department of Psychology, Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Bochum, Germany
| | - Thomas Forkmann
- Department of Clinical Psychology, University of Duisburg-Essen, Duisburg, Germany
| | - Heide Glaesmer
- Department of Medical Psychology and Medical Sociology, University of Leipzig, Leipzig, Germany
| | - Georg Juckel
- Department of Psychiatry, LWL-University Hospital, Ruhr-Universität Bochum, Bochum, Germany
| | - Laura Paashaus
- Department of Psychology, Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Bochum, Germany
| | - Dajana Rath
- Institute of Medical Psychology and Medical Sociology, University Hospital of RWTH Aachen University, Aachen, Germany
| | - Antje Schönfelder
- Department of Medical Psychology and Medical Sociology, University of Leipzig, Leipzig, Germany
| | - Dirk Moser
- Department of Genetic Psychology, Ruhr-Universität Bochum, Bochum, Germany
| | - Robert Kumsta
- Department of Genetic Psychology, Ruhr-Universität Bochum, Bochum, Germany
| | - Tobias Teismann
- Department of Psychology, Mental Health Research and Treatment Center, Ruhr-Universität Bochum, Bochum, Germany
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Chang HA, Fang WH, Liu YP, Tzeng NS, Shyu JF, Wan FJ, Huang SY, Chang TC, Chang CC. Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder. J Psychiatry Neurosci 2020; 45:379-386. [PMID: 32293839 PMCID: PMC7595742 DOI: 10.1503/jpn.190092] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Neuroticism personality trait is recognized as an important endophenotypic predictor of generalized anxiety disorder (GAD). Furthermore, endophenotype-based pathway approaches have recently been shown to have greater advantages for gene-finding strategies than traditional case-control studies. In the present study, in addition to conventional case-control methods, we used pathway analyses to test whether the tri-allelic serotonin transporter promoter polymorphism (combining 5-HTTLPR and rs25531) is associated with risk of GAD through its effects on trait neuroticism. METHODS We included 2236 Han Chinese adults in this study, including 736 patients with GAD and 1500 healthy participants. We genotyped the 5-HTTLPR and rs25531 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism method. We used the Neuroticism scale of the Maudsley Personality Inventory (MPI) short version (MPI-Neuroticism) to measure participants' tendency toward neuroticism. RESULTS Using endophenotype-based path analyses, we found significant indirect effects of the tri-allelic genotype on risk of GAD, mediated by MPI-Neuroticism in both men and women. Compared to women carrying the S'S' genotype, women carrying the L' allele had higher levels of MPI-Neuroticism, which in turn were associated with higher risk of GAD. Men, however, showed the opposite pattern. Using traditional case-control comparisons, we observed that the effect of tri-allelic genotype on GAD was significant, but only in women. LIMITATIONS Participants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism. CONCLUSION These findings are the first to show that the triallelic 5-HTTLPR polymorphism is associated with elevated risk of GAD, and that this effect is mediated via increased trait neuroticism, a sex-dependent risk pathway.
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Affiliation(s)
- Hsin-An Chang
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - Wen-Hui Fang
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - Yia-Ping Liu
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - Nian-Sheng Tzeng
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - Jia-Fwu Shyu
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - Fang-Jung Wan
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - San-Yuan Huang
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - Tieh-Ching Chang
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
| | - Chuan-Chia Chang
- From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, TriService General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu)
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35
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Hill SY, Jones BL, Haas GL. Suicidal ideation and aggression in childhood, genetic variation and young adult depression. J Affect Disord 2020; 276:954-962. [PMID: 32745832 PMCID: PMC7484359 DOI: 10.1016/j.jad.2020.07.049] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 06/01/2020] [Accepted: 07/05/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Suicidal thoughts and behaviors have been studied in association with a variety of risk factors. The aim of the present study was to determine if levels of child/adolescent aggression and/or variation in candidate genes previously associated with suicidal behaviors in adults would influence the presence of suicidal ideation in childhood/adolescence, and to determine if ideation was associated with young adult depression. METHODS A longitudinal study of children, adolescents and young adults who were at high or low risk for alcohol and other substance use disorders by familial background were assessed. The Child Behavior Checklist (CBCL) aggression scale scores with derived subtypes (physical and relational) and genetic variation (ANKK1, DRD2, COMT, SLC6A4, HTR2C) were used as predictors of the presence and onset of suicidal ideation in childhood using survival analysis. Structural equation models (SEM) were fit to determine the relative importance of the predictors controlling for background variables. RESULTS CBCL aggression was significantly associated with child/adolescent suicidal ideation. One SNP in the ANKK1 gene (rs1800497), one in the HTR2C gene (rs6318), and two haplotypes, AAAC in the ANKK1-DRD2 complex and the CCC haplotype of the HTR2C gene, were significantly associated with the presence and onset of child/adolescent suicidal ideation. Follow up in young adulthood showed a significant relationship between suicidal ideation in childhood/adolescence and young adult depression. CONCLUSIONS Genetic variation and presence of elevated aggression scores from the childhood CBCL are significant predictors of childhood suicidal ideation. Suicidal ideation in childhood and being female are predictors of young adult depression.
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Affiliation(s)
- Shirley Y. Hill
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 15213,Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA 15213,Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA USA 15213
| | - Bobby L. Jones
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 15213
| | - Gretchen L. Haas
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 15213,Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA 15213,VA Pittsburgh Healthcare System, Pittsburgh, PA USA 15213
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Schiele MA, Zwanzger P, Schwarte K, Arolt V, Baune BT, Domschke K. Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study. Int J Neuropsychopharmacol 2020; 24:191-199. [PMID: 33125470 PMCID: PMC7968622 DOI: 10.1093/ijnp/pyaa081] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/19/2020] [Accepted: 10/23/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in "pharmaco-epigenetic" approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients. METHODS The sample comprised n = 236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite- treated DNA extracted from blood cells. Patients were assessed over the course of a 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D). RESULTS Results confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions < 50%) and to furthermore be indicative of nonremission (HAM-D > 7). This also held true in a homogenous subgroup of patients continuously treated with selective serotonin reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors (n = 110). CONCLUSIONS Impaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision-making towards a more personalized treatment of MDD.
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Affiliation(s)
- M A Schiele
- Department of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - P Zwanzger
- kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany,Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - K Schwarte
- Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
| | - V Arolt
- Institute of Translational Psychiatry, Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
| | - B T Baune
- Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany,Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia,The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - K Domschke
- Department of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany,Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Germany,Correspondence: Katharina Domschke, MA, MD, PhD, Department of Psychiatry and Psychotherapy, University of Freiburg, Hauptstrasse 5, D-79104 Freiburg, Germany ()
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Ohrt TK, Perez M, Liew J, Hernández JC, Yu KY. The influence of temperament on stress-induced emotional eating in children. Obes Sci Pract 2020; 6:524-534. [PMID: 33082994 PMCID: PMC7556421 DOI: 10.1002/osp4.439] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 05/31/2020] [Accepted: 06/13/2020] [Indexed: 12/19/2022] Open
Abstract
Background Stress‐induced emotional eating is a risk factor for overweight and obesity. Previous research proposes both the human serotonin transporter gene (5‐HTTLPR) and child's reactive temperament are promising candidates to help explain individual differences in stress‐induced emotional eating and weight. Understanding the association between specific genotypes, reactive temperament factors, and stress‐induced emotional eating may inform the development of personalized and effective treatment for children who may be at risk for overweight and obesity. Objective The current study explored the conditional indirect effect of genetic and environmental susceptibility (i.e., the interaction between 5‐HTTLPR and reactive temperament) on weight (as measured by percent body fat) mediated by stress‐induced emotional eating. Method One hundred and forty‐seven children (4 to 6 years old; 50.3% female; 22.4% Hispanic), along with their primary caregiver, completed laboratory tasks and questionnaires that assessed the child's reactive temperament, stress‐induced emotional eating, and percent body fat. Results The interaction between 5‐HTTLPR and impulsivity as well as with negative affectivity significantly predicted percent body fat. The interaction between 5‐HTTLPR and impulsivity as well as with negative affectivity significantly predicted both total calorie consumption and rate of total calorie consumption. However, the mediation aspect of this statistical model was not supported. Conclusions Child reactive temperament is an important indicator of how children approach eating when stressed. Mental health providers may consider prescribing strategies to reduce emotional eating among children with the SL variant and moderate to high impulsivity as well as children with the LL variant and high negative affectivity.
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Affiliation(s)
| | - Marisol Perez
- Department of PsychologyArizona State UniversityTempeArizonaUSA
| | - Jeffrey Liew
- Department of Educational PsychologyTexas A&M UniversityCollege StationTexasUSA
| | | | - Kimberly Yim Yu
- Department of PsychologyArizona State UniversityTempeArizonaUSA
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Sinopoli VM, Erdman L, Burton CL, Easter P, Rajendram R, Baldwin G, Peterman K, Coste J, Shaheen SM, Hanna GL, Rosenberg DR, Arnold PD. Serotonin system gene variants and regional brain volume differences in pediatric OCD. Brain Imaging Behav 2020; 14:1612-1625. [PMID: 31187473 PMCID: PMC10521965 DOI: 10.1007/s11682-019-00092-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Obsessive-compulsive disorder (OCD) is phenotypically heterogeneous and genetically complex. This study aimed to reduce heterogeneity using structural brain imaging to study putative intermediate phenotypes for OCD. We hypothesized that select serotonin gene variants would differ in their relationship with brain volume in specific regions of the cortico-striato-thalamo-cortical (CSTC) circuits between OCD patients and controls. In a total of 200 pediatric subjects, we genotyped candidate serotonin genes (SLC6A4, HTR2A, HTR1B, and HTR2C) and conducted structural magnetic resonance imaging (sMRI) to measure regional brain volumes within CSTC circuits. In males and females separately, we first tested the association between serotonin gene variants and OCD and the effect of serotonin gene variants on brain volume irrespective of diagnosis. We then carried out a series of analyses to assess the effect of genotype-diagnosis interaction on brain volume. In females, but not in males, we identified a statistically significant genotype-diagnosis interaction for two single nucleotide polymorphisms (SNPs) in HTR2C, rs12860460 (interaction term estimate of 5.45 cc and interaction P value of 9.70e-8) and rs12854485 (interaction term estimate of 4.28 cc and interaction P value of 2.07e-6). The tested allele in each SNP was associated with decreased anterior cingulate cortex (ACC) volume in controls and with increased ACC volume in OCD patients. Our findings suggest that, in females, sequence variation in HTR2C influences ACC volume in pediatric OCD. The variants may contribute to differences in ACC volume and to OCD in a sex-specific manner when acting together with other genetic, biological, and/or environmental factors.
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Affiliation(s)
- Vanessa M Sinopoli
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Lauren Erdman
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
| | - Christie L Burton
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Phillip Easter
- Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA
| | | | - Gregory Baldwin
- Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA
| | - Kelli Peterman
- Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA
| | - Julie Coste
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - S-M Shaheen
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, University of Calgary, 4th floor, Teaching, Research and Wellness (TRW) Building, 3280 Hospital Dr NW, Calgary, AB, T2N 4Z6, ON, Canada
| | - Gregory L Hanna
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
| | - David R Rosenberg
- Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA
| | - Paul D Arnold
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
- Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, University of Calgary, 4th floor, Teaching, Research and Wellness (TRW) Building, 3280 Hospital Dr NW, Calgary, AB, T2N 4Z6, ON, Canada.
- Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, ON, Canada.
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Wongpaiboonwattana W, Plong-On O, Hnoonual A, Limprasert P. Significant associations between 5-hydroxytryptaminetransporter-linked promoter region polymorphisms of the serotonin transporter (solute carrier family 6 member 4) gene and Thai patients with autism spectrum disorder. Medicine (Baltimore) 2020; 99:e21946. [PMID: 32899028 PMCID: PMC7478716 DOI: 10.1097/md.0000000000021946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Autism spectrum disorder (ASD) is a form of pervasive developmental disorder manifested by impairment in social interactions and repetitive behaviors. Although genetic contribution is strongly suspected in autism, the specific genetic factors remain unidentified. Hyperserotoninemia has been reported in some autistic patients, and several studies have demonstrated an association between 5-hydroxytryptamine-transporter-linked promoter region (5-HTTLPR) polymorphisms and rs25531 single nucleotide polymorphism in the serotonin transporter gene (solute carrier family 6 member 4; SLC6A4) and ASD, indicating a possible involvement of the serotonin system in the etiology of ASD.To explore this situation further, a case-control association study of 5-HTTLPR and rs25531 polymorphisms on Thai ASD patients was conducted. A total of 188 ASD cases fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria (156 males and 32 females) and a total of 250 normal controls were recruited from the same ethnic backgrounds. 5-HTTLPR polymorphisms (Long, L; Short, S) and rs25531 (A/G) single nucleotide polymorphism were genotyped and compared between the patients and normal controls using chi-square statistics.The L/L genotype was more common in patients than in the controls (13.8% vs 5.2%, P = .006), and the LA haplotype was found in patients more than the controls (16.9% vs 12.2%, P = .048). When male patients were analyzed alone (156 individuals), the associations were also statistically significant with P = .017 for L/L genotype, and P = .019 for LA haplotype distribution.Our findings support previous reports suggesting an association between the 5-HTTLPR and rs25531 polymorphisms of SLC6A4 and patients with ASD.
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Affiliation(s)
| | - Oradawan Plong-On
- Department of Pathology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Areerat Hnoonual
- Department of Pathology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Pornprot Limprasert
- Faculty of Medicine, King Mongkut's Institute of Technology Ladkrabang, Bangkok
- Department of Pathology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
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40
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Widom CS, Miller D, Li X, Gordon D, Brzustowicz L. Childhood maltreatment, serotonin transporter gene, and risk for callous and unemotional traits: A prospective investigation. Psychiatry Res 2020; 291:113271. [PMID: 32629297 PMCID: PMC7484357 DOI: 10.1016/j.psychres.2020.113271] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 06/23/2020] [Accepted: 07/01/2020] [Indexed: 11/29/2022]
Abstract
Previous studies have reported associations between the serotonin transporter 5-HTTLPR genotype and antisocial and aggressive traits and between child maltreatment and antisocial traits. However, few studies have examined whether 5-HTTLPR moderates the influence of childhood maltreatment on callous and unemotional traits, a hallmark of psychopathy. Using a prospective cohort design, children with documented cases of maltreatment and matched controls were followed up and interviewed in adulthood. DNA was extracted from blood and saliva (N = 414) and callous-unemotional (CU) traits were assessed. Childhood maltreatment predicted higher CU scores in adulthood, whereas the effect of 5-HTTLPR was not significant. The effect of child maltreatment on CU traits did not differ by genetic risk (high or low activity 5-HTTLPR), whereas controls with the LL genotype had higher CU scores than controls with the SS genotype. Similar results were found for females and White, non-Hispanics, but not for males and Blacks. Variations in 5-HTTLPR did not affect the impact of child maltreatment on CU traits in adulthood. Genetic risk had a stronger effect on adults with lower environmental risk (controls). Having a history of child maltreatment or the LL genotype placed participants at risk for higher levels of callous and unemotional trait scores.
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Affiliation(s)
- Cathy Spatz Widom
- Psychology Department, John Jay College and Graduate Center, City University of New York, 524W. 59th Street, New York, NY 10019, USA.
| | - Dana Miller
- Psychology Department, John Jay College, City University of New York, 524W. 59th Street, New York, NY 10019, USA
| | - Xuechen Li
- Psychology Department, John Jay College, City University of New York, 524W. 59th Street, New York, NY 10019, USA
| | - Derek Gordon
- Department of Genetics and Human Genetics Institute, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854-8082, USA
| | - Linda Brzustowicz
- Department of Genetics and Human Genetics Institute, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854-8082, USA
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41
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Goldwaser EL, Miller CWT. The Genetic and Neural Circuitry Predictors of Benefit From Manualized or Open-Ended Psychotherapy. Am J Psychother 2020; 73:72-84. [DOI: 10.1176/appi.psychotherapy.20190041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Eric Luria Goldwaser
- Department of Psychiatry, University of Maryland Medical Center and Sheppard Pratt Health System, Baltimore
| | - Christopher W. T. Miller
- Department of Psychiatry, University of Maryland Medical Center and Sheppard Pratt Health System, Baltimore
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42
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Sicorello M, Dieckmann L, Moser D, Lux V, Luhmann M, Neubauer AB, Schlotz W, Kumsta R. Highs and lows: Genetic susceptibility to daily events. PLoS One 2020; 15:e0237001. [PMID: 32790782 PMCID: PMC7425846 DOI: 10.1371/journal.pone.0237001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 07/17/2020] [Indexed: 01/01/2023] Open
Abstract
Why people differ in their susceptibility to external events is essential to our understanding of personality, human development, and mental disorders. Genes explain a substantial portion of these differences. Specifically, genes influencing the serotonin system are hypothesized to be differential susceptibility factors, determining a person’s reactivity to both positive and negative environments. We tested whether genetic variation in the serotonin transporter (5-HTTLPR) is a differential susceptibility factor for daily events. Participants (N = 326, 77% female, mean age = 25, range = 17–36) completed smartphone questionnaires four times a day over four to five days, measuring stressors, uplifts, positive and negative affect. Affect was predicted from environment valence in the previous hour on a within-person level using three-level autoregressive linear mixed models. The 5-HTTLPR fulfilled all criteria of a differential susceptibility factor: Positive affect in carriers of the short allele (S) was less reactive to both uplifts and stressors, compared to homozygous carriers of the long allele (L/L). This pattern might reflect relative affective inflexibility in S-allele carriers. Our study provides insight into the serotonin system’s general role in susceptibility and highlights the need to assess the whole spectrum of naturalistic experiences.
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Affiliation(s)
- Maurizio Sicorello
- Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Germany
- Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Linda Dieckmann
- Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Germany
| | - Dirk Moser
- Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Germany
| | - Vanessa Lux
- Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Germany
| | - Maike Luhmann
- Department of Psychological Methods, Faculty of Psychology, Ruhr-University Bochum, Bochum, Germany
| | - Andreas B. Neubauer
- DIPF | Leibniz Institute for Research and Information in Education, Frankfurt am Main, Frankfurt, Germany
| | - Wolff Schlotz
- Max-Planck-Institute for Empirical Aesthetics, Frankfurt am Main, Frankfurt, Germany
- Institute of Psychology, Goethe University, Frankfurt am Main, Frankfurt, Germany
| | - Robert Kumsta
- Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Germany
- * E-mail:
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Sinopoli VM, Erdman L, Burton CL, Park LS, Dupuis A, Shan J, Goodale T, Shaheen SM, Crosbie J, Schachar RJ, Arnold PD. Serotonin system genes and hoarding with and without other obsessive-compulsive traits in a population-based, pediatric sample: A genetic association study. Depress Anxiety 2020; 37:760-770. [PMID: 32092211 DOI: 10.1002/da.22996] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 11/20/2019] [Accepted: 12/17/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hoarding, originally only considered a symptom of obsessive-compulsive disorder (OCD), is now categorized as a separate disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). We studied candidate serotonergic genes and the distinctness of hoarding in children and adolescents and hypothesized that unique gene variants would be associated with hoarding alone. METHODS We examined obsessive-compulsive (OC) traits, including hoarding, in a total of 5,213 pediatric participants in the community. We genotyped candidate serotonin genes (5-HTTLPR polymorphism in SLC6A4 for 2,018 individuals and single nucleotide polymorphisms [SNPs] across genes SLC6A4, HTR2A, and HTR1B for 4,711 individuals). In a previous study conducted by our group in the same sample, we identified a significant association between 5-HTTLPR and hoarding in males. In this study, we examined hoarding more closely by testing the association between serotonin gene variants and hoarding traits with and without other accompanying OC traits. RESULTS The [LG +S] variant in 5-HTTLPR was significantly associated with hoarding alone in males (p-value of 0.009). There were no significant findings for 5-HTTLPR in females. There were no significant findings after correction for multiple comparisons using SNP array data, but top SNP findings suggested that variation downstream of HTR1B may be implicated in hoarding alone in females. CONCLUSIONS Our results suggest specific serotonin gene variants are associated with hoarding traits alone, differing between sexes. Top findings are in line with our former study, suggesting that individuals with hoarding alone were driving previous results. Our paper supports hoarding disorder's new designation.
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Affiliation(s)
- Vanessa M Sinopoli
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Lauren Erdman
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Computer Science, University of Toronto, Toronto, ON, Canada
| | - Christie L Burton
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.,Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Laura S Park
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Annie Dupuis
- Clinical Research Services, The Hospital for Sick Children, Toronto, ON, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Janet Shan
- Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Tara Goodale
- Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - S-M Shaheen
- Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Jennifer Crosbie
- Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Russell J Schachar
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Paul D Arnold
- Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.,Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.,Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Licht CL, Mortensen EL, Hjordt LV, Stenbaek DS, Arentzen TE, Nørremølle A, Knudsen GM. Serotonin transporter gene (SLC6A4) variation and sensory processing sensitivity-Comparison with other anxiety-related temperamental dimensions. Mol Genet Genomic Med 2020; 8:e1352. [PMID: 32543106 PMCID: PMC7434600 DOI: 10.1002/mgg3.1352] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/01/2020] [Accepted: 05/19/2020] [Indexed: 12/16/2022] Open
Abstract
Background The short (s) allele of the 5‐HTTLPR polymorphism in the promoter region of the human serotonin transporter (5‐HTT) gene SLC6A4 has previously been associated with anxiety‐related personality dimensions. However, this relationship has not been confirmed in all studies and may be modified by environmental circumstances and/or psychiatric illness. This study examined whether the temperamental trait sensory processing sensitivity (SPS), characterized by increased responsivity to environmental stimuli, is related to 5‐HTTLPR/rs25531 genotype. Methods 5‐HTTLPR and rs25531 genotypes, level of SPS, self‐reported Revised NEO Personality Inventory (NEO‐PI‐R) and Temperament and Character Inventory (TCI) personality profiles, and symptoms of psychological distress (SCL‐90R Global Severity Index) were determined for 405 healthy volunteers. Results Sensory processing sensitivity was highly correlated with the anxiety‐related dimensions of the NEO‐PI‐R and the TCI models of personality, Neuroticism, and Harm Avoidance, respectively. However, the level of SPS was not associated with the combined 5‐HTTLPR and rs25531 s′/s′ genotype. Neuroticism and Harm Avoidance were also not associated with 5‐HTTLPR/rs25531 s′/s′ genotype. Correcting for symptoms of psychological distress had no effect on the relationships between personality and genotype. Conclusion The level of SPS was not associated with serotonin transporter gene variation. Further, combined 5‐HTTLPR and rs25531 genotype was not associated with other anxiety‐related dimensions.
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Affiliation(s)
- Cecilie L Licht
- Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen O, Denmark.,Unit of Medical Psychology, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen K, Denmark
| | - Erik L Mortensen
- Unit of Medical Psychology, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen K, Denmark
| | - Liv V Hjordt
- Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen O, Denmark
| | - Dea S Stenbaek
- Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen O, Denmark
| | - Tine E Arentzen
- Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen O, Denmark
| | - Anne Nørremølle
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Gitte M Knudsen
- Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen O, Denmark
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45
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Sun X, Li C, Zhong X, Dong D, Ming Q, Gao Y, Xiong G, Cheng C, Zhao H, Wang X, Yao S. Influence of psychosocial stress on activation in human brain regions: moderation by the 5-HTTLPR genetic locus. Physiol Behav 2020; 220:112876. [PMID: 32194071 DOI: 10.1016/j.physbeh.2020.112876] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 02/29/2020] [Accepted: 03/04/2020] [Indexed: 10/24/2022]
Abstract
Variants of the serotonin transporter linked polymorphic region (5-HTTLPR) of the serotonin transporter gene SLC6A4 have been related with the onset of depression, anxiety, and other mental disorders. Homozygotes for the short 5-HTTLPR variant, referred to as the SS genotype, have greater cortisol responses to experimentally induced psychosocial stress. In the current study, we used functional magnetic resonance imaging (fMRI) to compare regional brain activations across 5-HTTLPR genotypes in subjects performing the Montreal Imaging Stress Task (MIST). Subjects with an SS genotype had significant greater increases in cortisol concentrations after the task than subjects with at least one long 5-HTTLPR allele. Additionally, relative to L carriers, the SS group had greater activation in the dorsomedial prefrontal cortex(dmPFC), dorsal anterior cingulate cortex, anterior insula.
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Affiliation(s)
- Xiaoqiang Sun
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Chuting Li
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Xue Zhong
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Daifeng Dong
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Qingsen Ming
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Department of Psychiatry, The First Affiliated Hospital of Sochoow University, Suzhou, Jiangsu, China
| | - Yidian Gao
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Ge Xiong
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Chang Cheng
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Haofei Zhao
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Xiang Wang
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders
| | - Shuqiao Yao
- Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Medical Psychological Institute of Central South University, Changsha 410011, Hunan, China; National Clinical Research Center for Mental Disorders.
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Marshe VS, Islam F, Maciukiewicz M, Bousman C, Eyre HA, Lavretsky H, Mulsant BH, Reynolds CF, Lenze EJ, Müller DJ. Pharmacogenetic Implications for Antidepressant Pharmacotherapy in Late-Life Depression: A Systematic Review of the Literature for Response, Pharmacokinetics and Adverse Drug Reactions. Am J Geriatr Psychiatry 2020; 28:609-629. [PMID: 32122803 DOI: 10.1016/j.jagp.2020.01.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 01/14/2020] [Accepted: 01/15/2020] [Indexed: 02/06/2023]
Abstract
Affecting up to 15% of older adults, late-life depression (LLD) is characterized by the occurrence of depressive symptoms after the age of 50-65 years and maybe pathophysiologically distinct from depression in younger adults. Therefore, LLD is challenging to treat, and predictive genetic testing might be essential to improve treatment in this vulnerable population. The current review aims to provide a summary of the literature exploring genetic associations with antidepressant treatment outcomes in late-life. We conducted a systematic search of three integrated electronic databases. We identified 29 articles investigating genetic associations with antidepressant treatment outcomes, pharmacokinetic parameters, and adverse drug reactions in older adults. Given the small number of investigations conducted in older adults, it is difficult to conclude the presence or absence of genetic associations with the outcomes of interest. In sum, the most substantial amount of evidence exists for the CYP2D6 metabolizer status, SLC6A4 5-HTTLPR, and BDNF rs6265. These findings are consistent in the literature when not restricting to older adults, suggesting that similar treatment recommendations may be provided for older adults regarding genetic variation, such as those outlined for CYP2D6 by the Clinical Pharmacogenetics Implementation Consortium. Nonetheless, further studies are required in well-characterized samples, including genome-wide data, to validate if similar treatment adjustments are appropriate in older adults, given that there appear to be significant effects of genetic variation on antidepressant treatment factors.
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Affiliation(s)
- Victoria S Marshe
- Institute of Medical Science, University of Toronto (VSM, BHM, DJM), Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (VSM, FI, MM, BHM, DJM), Toronto, ON, Canada
| | - Farhana Islam
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (VSM, FI, MM, BHM, DJM), Toronto, ON, Canada; Department of Pharmacology (FI, DJM), University of Toronto, Toronto, ON, Canada
| | - Malgorzata Maciukiewicz
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (VSM, FI, MM, BHM, DJM), Toronto, ON, Canada
| | - Chad Bousman
- Departments of Medical Genetics, Psychiatry, and Physiology & Pharmacology (CB), University of Calgary, Calgary, AB, Canada; Department of Psychiatry (CB), University of Melbourne, Melbourne, Victoria, Australia
| | - Harris A Eyre
- Innovation Institute, Texas Medical Center (HAE), Houston, TX; School of Medicine, IMPACT SRC, Deakin University (HAE), Geelong, Victoria, Australia; Brainstorm Lab, Department of Psychiatry and Behavioral Sciences (HAE), Stanford University, Palo Alto, CA; Discipline of Psychiatry (HAE), The University of Adelaide, Adelaide, South Australia, Australia
| | - Helen Lavretsky
- Department of Psychiatry (HL), University of California, Los Angeles, CA
| | - Benoit H Mulsant
- Institute of Medical Science, University of Toronto (VSM, BHM, DJM), Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (VSM, FI, MM, BHM, DJM), Toronto, ON, Canada; Department of Psychiatry (BHM, DJM), University of Toronto, Toronto, ON, Canada
| | - Charles F Reynolds
- Department of Psychiatry (CFR), University of Pittsburgh, Pittsburgh, PA
| | - Eric J Lenze
- Healthy Mind Lab, Department of Psychiatry (EJL), Washington University, St. Louis, MO
| | - Daniel J Müller
- Institute of Medical Science, University of Toronto (VSM, BHM, DJM), Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (VSM, FI, MM, BHM, DJM), Toronto, ON, Canada; Department of Pharmacology (FI, DJM), University of Toronto, Toronto, ON, Canada; Department of Psychiatry (BHM, DJM), University of Toronto, Toronto, ON, Canada.
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Serotonin re-uptake transporter gene polymorphisms are associated with imatinib-induced diarrhoea in chronic myeloid leukaemia patients. Sci Rep 2020; 10:8394. [PMID: 32439979 PMCID: PMC7242433 DOI: 10.1038/s41598-020-65350-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 04/24/2020] [Indexed: 12/16/2022] Open
Abstract
Tyrosine kinase inhibitors (TKIs), the treatment of choice for chronic myeloid leukaemia (CML), can cause lower gastrointestinal (GI) toxicity which is manifested as diarrhoea. The mechanisms are not fully understood. The enteroendocrine signalling compound, serotonin (5-HT), is important for regulating peristaltic motion, fluid secretion and visceral hypersensitivity in the GI tract, and has been implicated in diseases such as irritable bowel syndrome. In this study, we have evaluated whether TKI-induced diarrhoea may be related to variation in the serotonin re-uptake transporter (SERT) gene. CML patients with and without diarrhoea on the SPIRIT2 trial (imatinib, n = 319; and dasatinib, n = 297) were genotyped for the promoter 5-HTTLPR, intron 2 VNTR and rs25531 polymorphisms by PCR-based methods. Diarrhoea was more prevalent in imatinib, than in dasatinib treated patients (P = 0.015), which when stratified by gender was seen to be driven by female patients (P = 0.036). Logistic regression analysis revealed that age, and the dominant HTTLPR with the rs25531 single nucleotide polymorphism (SNP) model, explained the occurrence of diarrhoea in ~10% of imatinib-treated female CML patients. These data suggest SERT polymorphisms influence imatinib-induced diarrhoea but not that of dasatinib.
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48
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The effect of serotonin transporter gene promoter polymorphism on adolescent and adult ADHD symptoms and educational attainment: A longitudinal study. Eur Psychiatry 2020; 28:372-8. [DOI: 10.1016/j.eurpsy.2012.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 04/25/2012] [Accepted: 04/26/2012] [Indexed: 02/02/2023] Open
Abstract
AbstractIntroduction:The purpose of this longitudinal study was to investigate the relationship between the 5-HTTLPR genotype, symptoms of ADHD in adolescence and adulthood, and educational attainment in a population representative sample. Neuroticism, depressive symptoms and general mental abilities were controlled for as possible confounding factors.Methods:ADHD symptoms were reported at age 15 and 18 by teachers using the Hyperactivity Scale of af Klinteberg and SNAP-IV, and self-reported at age 25 using the ASRS. Data about education were reported at age 25.Results:At age 15, subjects with the l/l genotype had more concentration difficulties compared to s-allele carriers, and they also had more inattention symptoms according to SNAP-IV at age 18. These results were not altered by taking neuroticism or depressive symptoms into account. No 5-HTTLPR genotype effect on self-reported ADHD symptoms at age 25 was found. Inattention symptoms in adolescence were associated with lower education in young adulthood. The proportion of subjects with higher education at age 25 was significantly larger among s/s genotype compared to the l/l or s/l genotype.Conclusions:The l/l genotype of the 5-HTTLPR is associated with inattentive symptoms during adolescence in the general population, and increases the likelihood of inferior educational level in young adulthood.
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Association between functional polymorphisms in serotonin transporter gene (SLC6A4) and escitalopram treatment response in depressive patients in a South Indian population. Eur J Clin Pharmacol 2020; 76:807-814. [DOI: 10.1007/s00228-020-02866-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 03/26/2020] [Indexed: 12/16/2022]
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Salinas V, Villarroel J, Silva H, Herrera L, Jerez S, Zazueta A, Montes C, Nieto R, Bustamante ML. SERT and BDNF polymorphisms interplay on neuroticism in borderline personality disorder. BMC Res Notes 2020; 13:61. [PMID: 32033618 PMCID: PMC7006183 DOI: 10.1186/s13104-020-4924-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 01/28/2020] [Indexed: 11/25/2022] Open
Abstract
Objective Genetic factors underlying different personality traits are not entirely understood, particularly how genes interact to modulate their effect. We studied 76 patients diagnosed with borderline personality disorder (BPD), characterized by extreme levels of personality traits, especially neuroticism (N), in which we genotyped two polymorphisms, the 5HTTLPR of the Serotonin transporter (SERT) gene, and the Val66Met of the Brain-derived neurotrophic factor (BDNF) gene. Results We found an association with SERT, where S-allele carriers had significantly higher levels of N than L-homozygous. Furthermore, we found that the protective effect of L-homozygosity is only evident on A-allele carriers of the BDNF Val66Met polymorphism. Genetic constitution in SERT and BDNF seems to be important in neuroticism, the most relevant personality trait on BPD.
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Affiliation(s)
- Valeria Salinas
- Neurogenetics Clinic and Laboratory, University Neurology Center and Neurology Section, J.M. Ramos Mejía, Hospital, Faculty of Medicine, Universidad de Buenos Aires, Buenos Aires, Argentina.,Precision Medicine and Clinical Genomics Program, Translational Medicine Research Institute, Faculty of Biomedical Sciences, Universidad Austral-CONICET, Buenos Aires, Argentina
| | - Juana Villarroel
- University Psychiatric Clinic, Clinical Hospital, Universidad de Chile, Santiago, Chile.,Department of Psychiatry and Mental Health, North Division, Faculty of Medicine, Universidad de Chile, Av. La Paz 1003, Recoleta, Santiago, Chile
| | - Hernán Silva
- University Psychiatric Clinic, Clinical Hospital, Universidad de Chile, Santiago, Chile.,Department of Psychiatry and Mental Health, North Division, Faculty of Medicine, Universidad de Chile, Av. La Paz 1003, Recoleta, Santiago, Chile
| | - Luisa Herrera
- Human Genetics Program, Biomedical Sciences Institute, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Sonia Jerez
- University Psychiatric Clinic, Clinical Hospital, Universidad de Chile, Santiago, Chile.,Department of Psychiatry and Mental Health, North Division, Faculty of Medicine, Universidad de Chile, Av. La Paz 1003, Recoleta, Santiago, Chile
| | - Alejandra Zazueta
- Program in Sciences and Engineering for Health, Universidad de Valparaíso, Valparaíso, Chile
| | - Cristián Montes
- University Psychiatric Clinic, Clinical Hospital, Universidad de Chile, Santiago, Chile.,Department of Psychiatry and Mental Health, North Division, Faculty of Medicine, Universidad de Chile, Av. La Paz 1003, Recoleta, Santiago, Chile
| | - Rodrigo Nieto
- University Psychiatric Clinic, Clinical Hospital, Universidad de Chile, Santiago, Chile.,Department of Psychiatry and Mental Health, North Division, Faculty of Medicine, Universidad de Chile, Av. La Paz 1003, Recoleta, Santiago, Chile.,Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - M Leonor Bustamante
- Department of Psychiatry and Mental Health, North Division, Faculty of Medicine, Universidad de Chile, Av. La Paz 1003, Recoleta, Santiago, Chile. .,Human Genetics Program, Biomedical Sciences Institute, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
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