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Bhagar R, Gill SS, Le-Niculescu H, Yin C, Roseberry K, Mullen J, Schmitz M, Paul E, Cooke J, Tracy C, Tracy Z, Gettelfinger AS, Battles D, Yard M, Sandusky G, Shekhar A, Kurian SM, Bogdan P, Niculescu AB. Next-generation precision medicine for suicidality prevention. Transl Psychiatry 2024; 14:362. [PMID: 39242534 PMCID: PMC11379963 DOI: 10.1038/s41398-024-03071-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 08/19/2024] [Accepted: 08/27/2024] [Indexed: 09/09/2024] Open
Abstract
Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.
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Affiliation(s)
- R Bhagar
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - S S Gill
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- MindX Sciences, Indianapolis, IN, USA
| | - H Le-Niculescu
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Psychiatry, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - C Yin
- University of Southern California, Los Angeles, CA, USA
| | - K Roseberry
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - J Mullen
- IT Core, Indiana University, Indianapolis, IN, USA
| | - M Schmitz
- MindX Sciences, Indianapolis, IN, USA
| | - E Paul
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- VA Medical Center, Indianapolis, IN, USA
| | - J Cooke
- VA Medical Center, Indianapolis, IN, USA
| | - C Tracy
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- VA Medical Center, Indianapolis, IN, USA
| | - Z Tracy
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- VA Medical Center, Indianapolis, IN, USA
| | - A S Gettelfinger
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
| | - D Battles
- Marion County Coroner's Office, Indianapolis, USA
| | - M Yard
- INBRAIN, Indianapolis, IN, USA
| | | | - A Shekhar
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
- Office of the Dean, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | - P Bogdan
- University of Southern California, Los Angeles, CA, USA
| | - A B Niculescu
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
- MindX Sciences, Indianapolis, IN, USA.
- VA Medical Center, Indianapolis, IN, USA.
- INBRAIN, Indianapolis, IN, USA.
- Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Psychiatry, University of Arizona College of Medicine, Phoenix, AZ, USA.
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De Simone S, Alfieri L, Bosco MA, Cantatore S, Carpinteri M, Cipolloni L, Neri M. The forensic aspects of suicide and neurotrophin factors: a research study. Front Pharmacol 2024; 15:1392832. [PMID: 39170712 PMCID: PMC11335659 DOI: 10.3389/fphar.2024.1392832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 07/26/2024] [Indexed: 08/23/2024] Open
Abstract
Introduction: Suicide represents a significant public health problem whose neurobiology is not yet fully understood. In many cases, suicidal behavior and psychiatric spectrum disorders are linked, in particular, to major depression. An emerging pathophysiological hypothesis underlines the role of neurotrophic factors, proteins involved in neurogenesis, in synaptic plasticity in response to stressors. Our research aims to evaluate the degree of expression of brain neurotrophic factor (BDNF) in brain areas involved in depressive disorder in suicidal subjects. Furthermore, we want to evaluate the expression of glial cell line-derived neurotrophic factor (GDNF) in suicidal subjects. Methods: We selected twenty confirmed cases of suicide among subjects with a clinical history of depressive pathology and possible psychopharmacological treatment, compared to ten controls of individuals who died of non-suicidal causes. For all selected cases and controls, immunohistochemical investigations were performed using a panel of antibodies against the BDNF and GDNF antigens on samples from the various brain areas. Results and discussion: The results show that BDNF was under-expressed in the cerebral parenchyma of subjects who died by suicide compared to controls, while there was an overexpression of GDNF in suicide victims, these data could be useful for a clinical application as potential markers for suicidal risk, to assess the severity of depression and development of specific pharmacological therapies for depression.
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Affiliation(s)
- Stefania De Simone
- Department of Clinical and Experimental Medicine, Section of Legal Medicine, University of Foggia, Foggia, Italy
| | - Letizia Alfieri
- Department of Medical Sciences, Section of Legal Medicine University of Ferrara, Ferrara, Italy
| | - Maria Antonella Bosco
- Department of Clinical and Experimental Medicine, Section of Legal Medicine, University of Foggia, Foggia, Italy
| | - Santina Cantatore
- Department of Clinical and Experimental Medicine, Section of Legal Medicine, University of Foggia, Foggia, Italy
| | - Michele Carpinteri
- Department of Biomedical, Metabolic and Neural Sciences, Institute of Legal Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Luigi Cipolloni
- Department of Clinical and Experimental Medicine, Section of Legal Medicine, University of Foggia, Foggia, Italy
| | - Margherita Neri
- Department of Medical Sciences, Section of Legal Medicine University of Ferrara, Ferrara, Italy
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Kari D, Mijiti P, Zou S, Zhang P. Study on the correlation between suicidal ideation and ABI3BP gene、DPYSL2 gene methylation in pediatric bipolar disorder with depressive episode. Heliyon 2024; 10:e23680. [PMID: 38226278 PMCID: PMC10788454 DOI: 10.1016/j.heliyon.2023.e23680] [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: 12/26/2022] [Revised: 11/27/2023] [Accepted: 12/09/2023] [Indexed: 01/17/2024] Open
Abstract
Patients with bipolar disorder have a higher risk of suicide than the general population. This study aimed to explore the correlation between suicide and gene methylation, as screened by genome-wide scanning, in children and adolescents with bipolar disorder. A total of 45 children and adolescents with bipolar disorder were divided into a suicidal ideation group (n = 41), a non-suicidal ideation group (n = 4), a low-risk group (n = 12), and a middle-to-high-risk group (n = 33). A pre-experiment was conducted on the suicidal ideation (n = 6) and non-suicidal ideation groups (n = 4). Blood samples were scanned using an Illumina HD 850K microarray, and methylation levels were analysed. Differential methylation sites among the sample groups were screened from the original data, and genes related to suicide were identified. Methylation of the ABI3BP and DPYSL2 genes was detected by pyrophosphate sequencing and statistically analysed. There was a significant difference in age between the low- and middle-risk groups. The results of GO analysis for the suicidal ideation and non-suicidal ideation groups showed that the differential methylation sites were mainly involved in the interferon-γ-mediated signalling pathway, with the main signalling pathways being the inflammatory bowel disease (IBD) pathway and type 1 diabetes mellitus (T1DM) pathway. There were significant differences in the methylation of ABI3BP, HLA-DQB1, HLA-DRB1, AUTS2, SP3, NINJ2, DPYSL2, and other genes between the suicidal and non-suicidal ideation groups. There was also a statistically significant difference in the gene methylation levels between the two groups. However, there was no significant difference in the degree of methylation of the ABI3BP and DPYSL2 genes between the low- and middle-to-high-risk groups. These results suggest that suicidal ideation is correlated with the methylation levels of differentially methylated genes in children with bipolar disorder. However, the severity of suicide risk in paediatric patients with bipolar disorder may not be correlated with the degree of methylation of the ABI3BP and DPYSL2 genes. Therefore, further validation was required.
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Affiliation(s)
- Dilinazi Kari
- Department of Clinical Psychology, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi Xinjiang, 830001, China
| | - Peierdun Mijiti
- Department of Epidemiology and Biostatistics, School of Public Health, Urumqi Xinjiang, 830001, China
| | - Shaohong Zou
- Department of Clinical Psychology, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi Xinjiang, 830001, China
| | - Peiwen Zhang
- Medical College, Shihezi University, Shihezi, Xinjiang, 832003, China
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Navarro D, Marín-Mayor M, Gasparyan A, García-Gutiérrez MS, Rubio G, Manzanares J. Molecular Changes Associated with Suicide. Int J Mol Sci 2023; 24:16726. [PMID: 38069051 PMCID: PMC10706600 DOI: 10.3390/ijms242316726] [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: 11/07/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual's vulnerability to suicide. These factors include various potential causes, from psychiatric disorders to genetic and epigenetic alterations. These changes can induce dysfunctions in crucial systems such as the serotonergic, cannabinoid, and hypothalamic-pituitary-adrenal axes. In addition, early life experiences of abuse can profoundly impact an individual's ability to cope with stress, ultimately leading to changes in the inflammatory system, which is a significant risk factor for suicidal behavior. Thus, it is clear that suicidal behavior may result from a confluence of multiple factors. This review examines the primary risk factors associated with suicidal behavior, including psychiatric disorders, early life adversities, and epigenetic modifications. Our goal is to elucidate the molecular changes at the genetic, epigenetic, and molecular levels in the brains of individuals who have taken their own lives and in the plasma and peripheral mononuclear cells of suicide attempters and how these changes may serve as predisposing factors for suicidal tendencies.
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Affiliation(s)
- Daniela Navarro
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (D.N.); (A.G.); (M.S.G.-G.)
- Redes de Investigación Cooperativa Orientada a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain;
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain
| | - Marta Marín-Mayor
- Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain;
- Department of Psychiatry, Complutense University of Madrid, 28040 Madrid, Spain
| | - Ani Gasparyan
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (D.N.); (A.G.); (M.S.G.-G.)
- Redes de Investigación Cooperativa Orientada a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain;
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain
| | - María Salud García-Gutiérrez
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (D.N.); (A.G.); (M.S.G.-G.)
- Redes de Investigación Cooperativa Orientada a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain;
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain
| | - Gabriel Rubio
- Redes de Investigación Cooperativa Orientada a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain;
- Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain;
- Department of Psychiatry, Complutense University of Madrid, 28040 Madrid, Spain
| | - Jorge Manzanares
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (D.N.); (A.G.); (M.S.G.-G.)
- Redes de Investigación Cooperativa Orientada a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain;
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain
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Dee G, Ryznar R, Dee C. Epigenetic Changes Associated with Different Types of Stressors and Suicide. Cells 2023; 12:cells12091258. [PMID: 37174656 PMCID: PMC10177343 DOI: 10.3390/cells12091258] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Stress is associated with various epigenetic changes. Some stress-induced epigenetic changes are highly dynamic, whereas others are associated with lasting marks on the epigenome. In our study, a comprehensive narrative review of the literature was performed by investigating the epigenetic changes that occur with acute stress, chronic stress, early childhood stress, and traumatic stress exposures, along with examining those observed in post-mortem brains or blood samples of suicide completers and attempters. In addition, the transgenerational effects of these changes are reported. For all types of stress studies examined, the genes Nr3c1, OXTR, SLC6A4, and BDNF reproducibly showed epigenetic changes, with some modifications observed to be passed down to subsequent generations following stress exposures. The aforementioned genes are known to be involved in neuronal development and hormonal regulation and are all associated with susceptibility to mental health disorders including depression, anxiety, personality disorders, and PTSD (post-traumatic stress disorder). Further research is warranted in order to determine the scope of epigenetic actionable targets in individuals suffering from the long-lasting effects of stressful experiences.
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Affiliation(s)
- Garrett Dee
- College of Osteopathic Medicine, Rocky Vista University, Parker, CO 80112, USA
| | - Rebecca Ryznar
- Molecular Biology, Department of Biomedical Sciences, Rocky Vista University, Parker, CO 80112, USA
| | - Colton Dee
- College of Osteopathic Medicine, Des Moines University, Des Moines, IA 50312, USA
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Epigenetic changes in the CYP2D6 gene are related to severity of suicide attempt: A cross-sectional study of suicide attempters. J Psychiatr Res 2023; 160:217-224. [PMID: 36857986 DOI: 10.1016/j.jpsychires.2023.02.025] [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: 10/21/2022] [Revised: 02/07/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023]
Abstract
BACKGROUND The ability to accurately estimate risk of suicide deaths on an individual level remains elusive. METHODS This study reports on a case-control study set-up from a well-characterized cohort of 88 predominantly female suicide attempters (SA), stratified into low- (n = 57) and high-risk groups (n = 31) based on reports of later death by suicide, as well as degree of intent-to-die and lethality of SA method. We perform an unbiased analysis of 12,930 whole-blood derived CpG-sites (Illumina Infinium EPIC BeadChip) previously demonstrated to be more conciliable with brain-derived variations. The candidate site was validated by pyrosequencing. External replication was performed in (1) relation to age at index suicide attempt in 97 women with emotionally unstable personality disorder (whole-blood) and (2) death by suicide in a mixed group of 183 prefrontal-cortex (PFC) derived samples who died by suicide or from non-psychiatric etiologies. RESULTS CYP2D6-coupled CpG-site cg07016288 was hypomethylated in severe suicidal behavior (p < 10E-06). Results were validated by pyrosequencing (p < 0.01). Replication analyses demonstrate hypomethylation of cg07016288 in relation to age at index SA in females (p < 0.05) and hypermethylation in PFC of male suicide completers (p < 0.05). LIMITATIONS Genotyping of CYP2D6 was not performed and CpG-site associations to gene expression were not explored. CONCLUSIONS CYP2D6-coupled epigenetic markers are hypomethylated in females in dependency of features known to confer increased risk of suicide deaths and hypermethylated in PFC of male suicide completers. Further elucidating the role of CYP2D6 in severe suicidality or suicide deaths hold promise to deduce clinically meaningful results.
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Kouter K, Zupanc T, Videtič Paska A. Targeted sequencing approach: Comprehensive analysis of DNA methylation and gene expression across blood and brain regions in suicide victims. World J Biol Psychiatry 2023; 24:12-23. [PMID: 35200087 DOI: 10.1080/15622975.2022.2046291] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/18/2022] [Accepted: 02/20/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVES Epigenetic mechanisms are involved in regulation of many pathologies, including suicidal behaviour. However, the factors through which epigenetics affect suicidal behaviour are not fully understood. METHODS We analysed DNA methylation of eight neuropsychiatric genes (NR3C1, SLC6A4, HTR1A, TPH2, SKA2, MAOA, GABRA1, and NRIP3) in brain regions (hippocampus, insula, amygdala, Brodmann area 46) and blood of 25 male suicide victims and 28 male control subjects, using bisulphite next-generation sequencing. RESULTS Comparing mean methylation values, notable changes were observed in NR3C1 (insula p-value = 0.05), HTR1A (insula p-value < 0.001, blood p-value = 0.001), SKA2 (insula p-value = 0.03, blood p-value = 0.016), MAOA (blood p-value < 0.001), GABRA1 (insula p-value = 0.05, blood p-value = 0.024) and NRIP3 (hippocampus p-value = 0.001, insula p-value = 0.002, amygdala p-value = 0.014). Comparing methylation pattern between blood and brain, similarity was observed between blood and insula for HTR1A. Gene expression analysis in hippocampus revealed changes in expression of NR3C1 (p-value = 0.049), SLC6A4 (p-value = 0.017) and HTR1A (p-value = 0.053). CONCLUSIONS Results provide an insight into the altered state of DNA methylation in suicidal behaviour. Epigenetic differences could therefore affect suicidal behaviour in both previously known and in novel neuropsychiatric candidate genes.
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Affiliation(s)
- Katarina Kouter
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tomaž Zupanc
- Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Alja Videtič Paska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Suicide and Neurotrophin Factors: A Systematic Review of the Correlation between BDNF and GDNF and Self-Killing. Healthcare (Basel) 2022; 11:healthcare11010078. [PMID: 36611538 PMCID: PMC9818650 DOI: 10.3390/healthcare11010078] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
According to WHO data, suicide is a public health priority. In particular, suicide is the fourth-leading cause of death in young people. Many risk factors of suicide are described, including individual-, relationship-, community-, and societal-linked ones. The leading factor is the diagnosis of mental illness. Nevertheless, not all people who attempt suicide are psychiatric patients; these characteristics help define high-risk populations. There are currently no useful biomarkers to indicate the risk of suicide. In recent years, neurotrophic factors have increasingly become of scientific interest. This review aims to summarize the current scientific knowledge on the correlation between BDNF and GDNF and suicide, to theorize whether neurotrophins could be a reliable marker for an early diagnosis of suicidal risk. The authors conducted a systematic review following PRISMA criteria. They found eight research papers in agreement with the inclusion criteria. According to the results of these studies, there may be a connection between BDNF brain levels and complete suicide, although there are discrepancies. A lack of interest in GDNF may suggest less involvement in the suicidal dynamic. Further studies may provide helpful information to researchers.
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Mirza S, Docherty AR, Bakian A, Coon H, Soares JC, Walss-Bass C, Fries GR. Genetics and epigenetics of self-injurious thoughts and behaviors: Systematic review of the suicide literature and methodological considerations. Am J Med Genet B Neuropsychiatr Genet 2022; 189:221-246. [PMID: 35975759 PMCID: PMC9900606 DOI: 10.1002/ajmg.b.32917] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/26/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023]
Abstract
Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.
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Affiliation(s)
- Salahudeen Mirza
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Institute of Child Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Anna R. Docherty
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA,Huntsman Mental Health Institute, Salt Lake City, Utah, USA,Department of Psychiatry, The Virginia Commonwealth University, Richmond, Virginia, USA
| | - Amanda Bakian
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA,Huntsman Mental Health Institute, Salt Lake City, Utah, USA
| | - Hilary Coon
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA,Huntsman Mental Health Institute, Salt Lake City, Utah, USA
| | - Jair C. Soares
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Consuelo Walss-Bass
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Gabriel R. Fries
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA,Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA
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10
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Gonçalves de Andrade E, González Ibáñez F, Tremblay MÈ. Microglia as a Hub for Suicide Neuropathology: Future Investigation and Prevention Targets. Front Cell Neurosci 2022; 16:839396. [PMID: 35663424 PMCID: PMC9158339 DOI: 10.3389/fncel.2022.839396] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 02/22/2022] [Indexed: 12/27/2022] Open
Abstract
Suicide is a complex public health challenge associated worldwide with one death every 40 s. Research advances in the neuropathology of suicidal behaviors (SB) have defined discrete brain changes which may hold the key to suicide prevention. Physiological differences in microglia, the resident immune cells of the brain, are present in post-mortem tissue samples of individuals who died by suicide. Furthermore, microglia are mechanistically implicated in the outcomes of important risk factors for SB, including early-life adversity, stressful life events, and psychiatric disorders. SB risk factors result in inflammatory and oxidative stress activities which could converge to microglial synaptic remodeling affecting susceptibility or resistance to SB. To push further this perspective, in this Review we summarize current areas of opportunity that could untangle the functional participation of microglia in the context of suicide. Our discussion centers around microglial state diversity in respect to morphology, gene and protein expression, as well as function, depending on various factors, namely brain region, age, and sex.
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Affiliation(s)
- Elisa Gonçalves de Andrade
- Neuroscience Graduate Program, Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Fernando González Ibáñez
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
- *Correspondence: Marie-Ève Tremblay,
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Piras IS, Huentelman MJ, Pinna F, Paribello P, Solmi M, Murru A, Carpiniello B, Manchia M, Zai CC. A review and meta-analysis of gene expression profiles in suicide. Eur Neuropsychopharmacol 2022; 56:39-49. [PMID: 34923210 DOI: 10.1016/j.euroneuro.2021.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/30/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022]
Abstract
Suicide claims over 800,000 deaths worldwide, making it a serious public health problem. The etiopathophysiology of suicide remains unclear and is highly complex, and postmortem gene expression studies can offer insights into the molecular biological mechanism underlying suicide. In the current study, we conducted a meta-analysis of postmortem brain gene expression in relation to suicide. We identified five gene expression datasets for postmortem orbitofrontal, prefrontal, or dorsolateral prefrontal cortical brain regions from the Gene Expression Omnibus repository. After quality control, the total sample size was 380 (141 suicide deaths and 239 deaths from other causes). We performed the analyses using two meta-analytic approaches. We further performed pathway and cell-set enrichment analyses. We found reduced expression of the KCNJ2 (Potassium Inwardly Rectifying Channel Subfamily J Member 2), A2M (Alpha-2-Macroglobulin), AGT (Angiotensinogen), PMP2 (Peripheral Myelin Protein 2), and VEZF1 (Vascular Endothelial Zinc Finger 1) genes (FDR p<0.05). Our findings support the involvement of astrocytes, stress response, immune system, and microglia in suicide. These findings will require further validation in additional large datasets.
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Affiliation(s)
- Ignazio S Piras
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, United States
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, United States
| | - Federica Pinna
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
| | - Pasquale Paribello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
| | - Marco Solmi
- Department of Psychiatry, University of Ottawa, Ontario, Canada; Department of Mental Health, The Ottawa Hospital, Ontario, Canada; Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program University of Ottawa Ottawa Ontario; Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, King's College London, London, United Kingdom
| | - Andrea Murru
- Bipolar and Depression Disorders Unit, Institute of Neuroscience, Hospital Clinic, IDIBAPS CIBERSAM, University of Barcelona, Barcelona, Catalonia, Spain
| | - Bernardo Carpiniello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
| | - Mirko Manchia
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
| | - Clement C Zai
- Neurogenetics Section, Molecular Brain Science, Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, Institute of Medical Science, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, United States
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12
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Ropret S, Kouter K, Zupanc T, Videtic Paska A. BDNF methylation and mRNA expression in brain and blood of completed suicides in Slovenia. World J Psychiatry 2021; 11:1301-1313. [PMID: 35070779 PMCID: PMC8717036 DOI: 10.5498/wjp.v11.i12.1301] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Suicide is a major public health problem. Worldwide, around 800000 people die by suicide every year. Suicide is a multifactorial disorder, with numerous environmental and genetic risk factors involved. Among the candidate genes, changes in the BDNF locus at the gene, epigenetic, mRNA, and protein expression levels have been implicated in psychiatric disorders, including suicidal behavior and completed suicides. AIM To investigate changes in BDNF methylation and expression of four alternative BDNF transcripts for association with completed suicide. METHODS This case-control study included 42 unrelated male Caucasian subjects, where 20 were control subjects who died following acute cardiac arrest, and 22 were suicide victims who died by hanging. DNA and RNA were extracted from brain tissue (Brodmann area 9 and hippocampus) and from blood. DNA methylation and mRNA expression levels were determined by targeted bisulfite next-generation sequencing and reverse-transcription quantitative PCR. Statistical analysis was done by use of two-tailed Student's t tests for two independent samples, and the Benjamini-Hochberg procedure was implemented for correction for multiple comparisons. RESULTS In DNA from brain tissue, there were no significant differences in BDNF methylation between the study groups. However, data showed significantly reduced DNA methylation of the BDNF region upstream of exon I in blood samples of suicide victims compared to the controls (5.67 ± 0.57 vs 6.83 ± 0.64, P corr = 0.01). In Brodmann area 9 of the brain of the suicide victims but not in their hippocampus, there was higher expression of BDNF transcript I-IX (NM_170731.4) compared to the controls (0.077 ± 0.024 vs 0.05 ± 0.013, P = 0.042). In blood, expression analysis for the BDNF transcripts was not feasible due to extensive RNA degradation. CONCLUSION Despite the limitations of the study, the obtained data further support a role for BDNF in suicidality. However, it should be noted that suicidal behavior is a multifactorial disorder with numerous environmental and genetic risk factors involved.
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Affiliation(s)
- Sandra Ropret
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Katarina Kouter
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Tomaž Zupanc
- Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Alja Videtic Paska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
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13
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Liu L, Hu Y, Lu Y, Hu L, Gao C, Nie S. Sex-dependent DNA hypermethylation of SLC6A4 in patients with schizophrenia. Neurosci Lett 2021; 769:136394. [PMID: 34910986 DOI: 10.1016/j.neulet.2021.136394] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 12/02/2021] [Accepted: 12/08/2021] [Indexed: 01/02/2023]
Abstract
Schizophrenia (SCZ) is a mental health condition with a complex pathogenic mechanism. One important hypothesis of SCZ pathology is serotonin (5-HT) impairment, and the 5-HT transporter, encoded by the SLC6A4 gene, plays a key role in regulating 5-HT levels. Some studies have confirmed that the CpG island upstream of exon 1 and the island shore region of SLC6A4 are hypermethylated in SCZ; however, to the best of our knowledge, there has been no study on the methylation level of CpG islands downstream of SLC6A4 exon 1. Methylation of CpG islands downstream of SLC6A4 exon 1 was measured in the peripheral blood of SCZ patients with positive symptoms using the MethylTarget method. Overall, the methylation level of SLC6A4 was significantly higher in women than in men. In intergroup comparisons, the level of SLC6A4 methylation was higher in the SCZ group than in the control group, especially within the male subgroup. Moreover, methylation levels of several CpG sites correlated significantly with SCZ. These results suggest that epigenetic alterations of SLC6A4 are related to SCZ pathophysiology. These findings improve the current understanding of the role of the 5-HT system in the pathological development of SCZ.
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Affiliation(s)
- Linlin Liu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, PR China
| | - Yi Hu
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, PR China
| | - Yumei Lu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, PR China
| | - Liping Hu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, PR China.
| | - Changqing Gao
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, PR China.
| | - Shengjie Nie
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, PR China.
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14
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Cahill B, Poelker-Wells S, Prather JF, Li Y. A Glimpse Into the Sexual Dimorphisms in Major Depressive Disorder Through Epigenetic Studies. Front Neural Circuits 2021; 15:768571. [PMID: 34744641 PMCID: PMC8564393 DOI: 10.3389/fncir.2021.768571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 09/28/2021] [Indexed: 11/13/2022] Open
Abstract
Depression is an umbrella term used to describe a mood disorder with a broad spectrum of symptoms including a persistent feeling of sadness, loss of interest, and deficits in social behavior. Epigenetic research bridges the environmental and genetic landscape and has the potential to exponentially improve our understanding of such a complex disorder. Depression is also a sexually dimorphic disorder and variations exist within epigenetic modification sites between sexes. These sex-specific mediators may impact behavioral symptomology and could serve as therapeutic targets for treatments to improve behavioral deficits. This mini review will focus on the social behavior perspective of depression and specifically explore the sexually different epigenetic modifications on depression.
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Affiliation(s)
- Branden Cahill
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY, United States
| | - Samuel Poelker-Wells
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY, United States
| | - Jonathan F Prather
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY, United States
| | - Yun Li
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY, United States
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15
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Kouter K, Videtic Paska A. 'Omics' of suicidal behaviour: A path to personalised psychiatry. World J Psychiatry 2021; 11:774-790. [PMID: 34733641 PMCID: PMC8546767 DOI: 10.5498/wjp.v11.i10.774] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 07/16/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Psychiatric disorders, including suicide, are complex disorders that are affected by many different risk factors. It has been estimated that genetic factors contribute up to 50% to suicide risk. As the candidate gene approach has not identified a gene or set of genes that can be defined as biomarkers for suicidal behaviour, much is expected from cutting edge technological approaches that can interrogate several hundred, or even millions, of biomarkers at a time. These include the '-omic' approaches, such as genomics, transcriptomics, epigenomics, proteomics and metabolomics. Indeed, these have revealed new candidate biomarkers associated with suicidal behaviour. The most interesting of these have been implicated in inflammation and immune responses, which have been revealed through different study approaches, from genome-wide single nucleotide studies and the micro-RNA transcriptome, to the proteome and metabolome. However, the massive amounts of data that are generated by the '-omic' technologies demand the use of powerful computational analysis, and also specifically trained personnel. In this regard, machine learning approaches are beginning to pave the way towards personalized psychiatry.
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Affiliation(s)
- Katarina Kouter
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Alja Videtic Paska
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana SI-1000, Slovenia
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16
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Romero-Pimentel AL, Almeida D, Muñoz-Montero S, Rangel C, Mendoza-Morales R, Gonzalez-Saenz EE, Nagy C, Chen G, Aouabed Z, Theroux JF, Turecki G, Martinez-Levy G, Walss-Bass C, Monroy-Jaramillo N, Fernández-Figueroa EA, Gómez-Cotero A, García-Dolores F, Morales-Marin ME, Nicolini H. Integrative DNA Methylation and Gene Expression Analysis in the Prefrontal Cortex of Mexicans Who Died by Suicide. Int J Neuropsychopharmacol 2021; 24:935-947. [PMID: 34214149 PMCID: PMC8653872 DOI: 10.1093/ijnp/pyab042] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/04/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Suicide represents a major health concern, especially in developing countries. While many demographic risk factors have been proposed, the underlying molecular pathology of suicide remains poorly understood. A body of evidence suggests that aberrant DNA methylation and expression is involved. In this study, we examined DNA methylation profiles and concordant gene expression changes in the prefrontal cortex of Mexicans who died by suicide. METHODS In collaboration with the coroner's office in Mexico City, brain samples of males who died by suicide (n = 35) and age-matched sudden death controls (n = 13) were collected. DNA and RNA were extracted from prefrontal cortex tissue and analyzed with the Infinium Methylation480k and the HumanHT-12 v4 Expression Beadchips, respectively. RESULTS We report evidence of altered DNA methylation profiles at 4430 genomic regions together with 622 genes characterized by differential expression in cases vs controls. Seventy genes were found to have concordant methylation and expression changes. Metacore-enriched analysis identified 10 genes with biological relevance to psychiatric phenotypes and suicide (ADCY9, CRH, NFATC4, ABCC8, HMGA1, KAT2A, EPHA2, TRRAP, CD22, and CBLN1) and highlighted the association that ADCY9 has with various pathways, including signal transduction regulated by the cAMP-responsive element modulator, neurophysiological process regulated by the corticotrophin-releasing hormone, and synaptic plasticity. We therefore went on to validate the observed hypomethylation of ADCY9 in cases vs control through targeted bisulfite sequencing. CONCLUSION Our study represents the first, to our knowledge, analysis of DNA methylation and gene expression associated with suicide in a Mexican population using postmortem brain, providing novel insights for convergent molecular alterations associated with suicide.
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Affiliation(s)
- Ana L Romero-Pimentel
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico,McGill Group of Suicide Studies, Montreal,Canada
| | - Daniel Almeida
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Said Muñoz-Montero
- Facultad de Psicología, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Claudia Rangel
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Roberto Mendoza-Morales
- Instituto de Ciencias Forenses del Tribunal Superior de Justicia de la CDMX, Mexico City, Mexico
| | - Eli E Gonzalez-Saenz
- Instituto de Ciencias Forenses del Tribunal Superior de Justicia de la CDMX, Mexico City, Mexico
| | - Corina Nagy
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Gary Chen
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Zahia Aouabed
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | | | - Gustavo Turecki
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Gabriela Martinez-Levy
- Psychiatric Genetics Department, Clinical Research Branch, National Institute of Psychiatry Ramón de la Fuente, Mexico City, Mexico
| | - Consuelo Walss-Bass
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas,USA
| | - Nancy Monroy-Jaramillo
- Department of Neurogenetics, National Institute of Neurology and Neurosurgery, Manuel Velasco Suarez, Mexico City, Mexico
| | | | - Amalia Gómez-Cotero
- Centro Interdisciplinario de Ciencias de la Salud, Instituto Politécnico Nacional, Unidad Santo Tomás, Mexico City, Mexico
| | - Fernando García-Dolores
- Instituto de Ciencias Forenses del Tribunal Superior de Justicia de la CDMX, Mexico City, Mexico
| | | | - Humberto Nicolini
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico,Correspondence: José Humberto Nicolini Sánchez, MD, PhD, Laboratorio de Genómica de Enfermedades Psiquiátricas y neurodegenerativas, Instituto Nacional de Medicina Genómica, Periférico Sur 4809, Arenal Tepepan, Tlalpan, 14610, Ciudad de México, CDMX, México ()
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17
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Krzyżanowska M, Rębała K, Steiner J, Kaliszan M, Pieśniak D, Karnecki K, Wiergowski M, Brisch R, Braun K, Jankowski Z, Kosmowska M, Chociej J, Gos T. Reduced ribosomal DNA transcription in the prefrontal cortex of suicide victims: consistence of new molecular RT-qPCR findings with previous morphometric data from AgNOR-stained pyramidal neurons. Eur Arch Psychiatry Clin Neurosci 2021; 271:567-576. [PMID: 33501518 PMCID: PMC7981327 DOI: 10.1007/s00406-021-01232-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/11/2021] [Indexed: 12/12/2022]
Abstract
Prefrontal cortical regions play a key role in behavioural regulation, which is profoundly disturbed in suicide. The study was carried out on frozen cortical samples from the anterior cingulate cortex (dorsal and ventral parts, ACd and ACv), the orbitofrontal cortex (OFC), and the dorsolateral cortex (DLC) obtained from 20 suicide completers (predominantly violent) with unknown psychiatric diagnosis and 21 non-suicidal controls. The relative level of ribosomal RNA (rRNA) as a marker of the transcriptional activity of ribosomal DNA (rDNA) was evaluated bilaterally in prefrontal regions mentioned above (i.e. in eight regions of interest, ROIs) by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The overall statistical analysis revealed a decrease in rDNA activity in suicide victims versus controls, particularly in male subjects. Further ROI-specific post hoc analyses revealed a significant decrease in this activity in suicides compared to non-suicides in five ROIs. This effect was accentuated in the ACv, where it was observed bilaterally. Our findings suggest that decreased rDNA transcription in the prefrontal cortex plays an important role in suicide pathogenesis and corresponds with our previous morphometric analyses of AgNOR-stained neurons.
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Affiliation(s)
- Marta Krzyżanowska
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Krzysztof Rębała
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Johann Steiner
- grid.5807.a0000 0001 1018 4307Department of Psychiatry, Otto von Guericke University, Magdeburg, Germany
| | - Michał Kaliszan
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Dorota Pieśniak
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Karol Karnecki
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Marek Wiergowski
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Ralf Brisch
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Katharina Braun
- grid.5807.a0000 0001 1018 4307Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University, Magdeburg, Germany
| | - Zbigniew Jankowski
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Monika Kosmowska
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Joanna Chociej
- grid.11451.300000 0001 0531 3426Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204 Gdańsk, Poland
| | - Tomasz Gos
- Department of Forensic Medicine, Medical University of Gdańsk, ul. Dębowa 23, 80-204, Gdańsk, Poland. .,Department of Psychiatry, Otto von Guericke University, Magdeburg, Germany. .,Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto von Guericke University, Magdeburg, Germany.
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18
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Misztak P, Pańczyszyn-Trzewik P, Nowak G, Sowa-Kućma M. Epigenetic marks and their relationship with BDNF in the brain of suicide victims. PLoS One 2020; 15:e0239335. [PMID: 32970734 PMCID: PMC7513998 DOI: 10.1371/journal.pone.0239335] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022] Open
Abstract
Background Suicide is a common phenomenon affecting people of all ages. There is a strong relationship between suicidal ideation and depressive disorders. Increasing number of studies suggest that epigenetic modifications in certain brain areas are the main mechanism through which environmental and genetic factors interact with each other contributing to the development of mental disorders. To verify this hypothesis, some epigenetic marks: H3K9/14ac, HDAC2/3, H3K27me2 and Sin3a, as well as p-S421-MeCP2/MeCP2 were examined. On the other hand, BDNF protein level were studied. Materials and methods Western blot analysis were performed in the frontal cortex (FCx) and hippocampus (HP) of suicide victims (n = 14) and non-suicidal controls (n = 8). The differences between groups and correlations between selected proteins were evaluated using Mann-Whitney U-test and Spearman’s rank correlation. Results Statistically significant decrease in H3K9/14ac (FCx:↓~23%;HP:↓~33%) combined with increase in HDAC3 (FCx:↑~103%;HP:↑~85% in HP) protein levels in suicides compared to the controls was shown. These alterations were accompanied by an increase in H3K27me2 (FCx:↑45%;HP:↑~59%) and Sin3a (HP:↑50%) levels and decrease in p-S421-MeCP2/MeCP2 protein ratio (HP:↓~55%;FCx:↓~27%). Moreover, reduced BDNF protein level (FCx:↓~43%;HP:↓~28%) in suicides was observed. On the other hand, some significant correlations (e.g. between H3K9/14ac and HDAC2 or between BDNF and p-S421-MeCP2/MeCP2) were demonstrated. Conclusions Our findings confirm the role of epigenetic component and BDNF protein in suicidal behavior. Lowered BDNF protein level in suicides is probably due to decrease in histone acetylation and increased level of factors related with deacetylation and methylation processes, including MeCP2 factor, which may operate bidirectionally (an activator or inhibitor of transcription).
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Affiliation(s)
- Paulina Misztak
- Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
- Chair of Pharmacobiology, Jagiellonian University Medical College, Krakow, Poland
| | - Patrycja Pańczyszyn-Trzewik
- Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
- Department of Human Physiology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Gabriel Nowak
- Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
- Chair of Pharmacobiology, Jagiellonian University Medical College, Krakow, Poland
| | - Magdalena Sowa-Kućma
- Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
- Department of Human Physiology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
- * E-mail: ,
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19
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Vargas-Medrano J, Diaz-Pacheco V, Castaneda C, Miranda-Arango M, Longhurst MO, Martin SL, Ghumman U, Mangadu T, Chheda S, Thompson PM, Gadad BS. Psychological and neurobiological aspects of suicide in adolescents: Current outlooks. Brain Behav Immun Health 2020; 7:100124. [PMID: 32835300 PMCID: PMC7405877 DOI: 10.1016/j.bbih.2020.100124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 01/10/2023] Open
Abstract
Suicidality is one of the leading causes of death among young adults in the United States and represents a significant health problem worldwide. The suicide rate among adolescents in the United States has increased dramatically in the latest years and has been accompanied by considerable changes in youth suicide, especially among young girls. Henceforth, we need a good understanding of the risk factors contributing to suicidal behavior in youth. An explanatory model for suicidal behavior that links clinical and psychological risk factors to the underlying neurobiological, neuropsychological abnormalities related to suicidal behavior might predict to help identify treatment options and have empirical value. Our explanatory model proposes that developmental, biological factors (genetics, proteomics, epigenetics, immunological) and psychological or clinical (childhood adversities) may have causal relevance to the changes associated with suicidal behavior. In this way, our model integrates findings from several perspectives in suicidality and attempts to explain the relationship between various neurobiological, genetic, and clinical observations in suicide research, offering a comprehensive hypothesis to facilitate understanding of this complex outcome. Unraveling the knowledge of the complex interplay of psychological, biological, sociobiological, and clinical risk factors is highly essential, concerning the development of effective prevention strategy plans for suicidal ideation and suicide.
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Affiliation(s)
- Javier Vargas-Medrano
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
- Southwest Brain Bank, Texas Tech University Health Science Center, El Paso, TX, 79905, University of Texas, El Paso, USA
| | - Valeria Diaz-Pacheco
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
- Southwest Brain Bank, Texas Tech University Health Science Center, El Paso, TX, 79905, University of Texas, El Paso, USA
| | - Christopher Castaneda
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
| | - Manuel Miranda-Arango
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, TX, 79968, USA
| | - Melanie O Longhurst
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
| | - Sarah L. Martin
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
| | - Usman Ghumman
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
| | - Thenral Mangadu
- Minority AIDS Research Center, Department of Health Sciences, The University of Texas at El Paso, TX, 79968, USA
| | - Sadhana Chheda
- Department of Pediatrics, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
| | - Peter M. Thompson
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
- Southwest Brain Bank, Texas Tech University Health Science Center, El Paso, TX, 79905, University of Texas, El Paso, USA
| | - Bharathi S. Gadad
- Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, 79905, USA
- Southwest Brain Bank, Texas Tech University Health Science Center, El Paso, TX, 79905, University of Texas, El Paso, USA
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20
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Ikegame T, Bundo M, Okada N, Murata Y, Koike S, Sugawara H, Saito T, Ikeda M, Owada K, Fukunaga M, Yamashita F, Koshiyama D, Natsubori T, Iwashiro N, Asai T, Yoshikawa A, Nishimura F, Kawamura Y, Ishigooka J, Kakiuchi C, Sasaki T, Abe O, Hashimoto R, Iwata N, Yamasue H, Kato T, Kasai K, Iwamoto K. Promoter Activity-Based Case-Control Association Study on SLC6A4 Highlighting Hypermethylation and Altered Amygdala Volume in Male Patients With Schizophrenia. Schizophr Bull 2020; 46:1577-1586. [PMID: 32556264 PMCID: PMC7846196 DOI: 10.1093/schbul/sbaa075] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.
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Affiliation(s)
- Tempei Ikegame
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Miki Bundo
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan,PRESTO, Japan Science and Technology Agency, Tokyo, Japan
| | - Naohiro Okada
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo, Japan
| | - Yui Murata
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shinsuke Koike
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,UTokyo Institute for Diversity and Adaptation of Human Mind (UTIDAHM), The University of Tokyo, Tokyo, Japan
| | - Hiroko Sugawara
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takeo Saito
- Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan
| | - Masashi Ikeda
- Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan
| | - Keiho Owada
- Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaki Fukunaga
- Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan
| | - Fumio Yamashita
- Division of Ultrahigh Field MRI, Institute for Biomedical Sciences, Iwate Medical University, Iwate, Japan
| | - Daisuke Koshiyama
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsunobu Natsubori
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norichika Iwashiro
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsuro Asai
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akane Yoshikawa
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Fumichika Nishimura
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | | | - Chihiro Kakiuchi
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tsukasa Sasaki
- Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan
| | - Osamu Abe
- Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Hashimoto
- Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan,Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Nakao Iwata
- Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan
| | - Hidenori Yamasue
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN CBS, Saitama, Japan
| | - Kiyoto Kasai
- Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuya Iwamoto
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan,To whom correspondence should be addressed; Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan; tel: +81-96-373-5062, fax: +81-96-373-5062, e-mail:
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21
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Cheung S, Woo J, Maes MS, Zai CC. Suicide epigenetics, a review of recent progress. J Affect Disord 2020; 265:423-438. [PMID: 32090769 DOI: 10.1016/j.jad.2020.01.040] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/17/2019] [Accepted: 01/11/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Suicide results in over 800,000 deaths every year, making it a major public health concern worldwide. It is highly complex, with genetic and environmental influences. Epigenetic mechanisms, including DNA methylation, miRNA, and histone modifications, could explain the complex interplay of environmental risk factors with genetic risk factors in the emergence of suicidal behavior. METHODS Here, we review the literature on suicide epigenetics over the past 10 years. RESULTS There has been significant progress in the field of suicide epigenetics, with emerging findings in the brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis genes. LIMITATIONS Studying patient subgroups is needed in order to extract more comparable and reproducible epigenetic findings in suicide. CONCLUSIONS It is crucial to consider suicidal patients or suicide victims' distal and proximal past history e.g., early-life adversity and psychiatric disorder in epigenetic studies of suicidality.
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Affiliation(s)
- Serina Cheung
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada
| | - Julia Woo
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; Faculty of Medicine, University of Toronto, Canada
| | - Miriam S Maes
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada
| | - Clement C Zai
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Canada; Institute of Medical Science, University of Toronto, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Canada; Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
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22
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Policicchio S, Washer S, Viana J, Iatrou A, Burrage J, Hannon E, Turecki G, Kaminsky Z, Mill J, Dempster EL, Murphy TM. Genome-wide DNA methylation meta-analysis in the brains of suicide completers. Transl Psychiatry 2020; 10:69. [PMID: 32075955 PMCID: PMC7031296 DOI: 10.1038/s41398-020-0752-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/09/2020] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality.
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Affiliation(s)
- Stefania Policicchio
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Sam Washer
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Joana Viana
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Artemis Iatrou
- grid.240684.c0000 0001 0705 3621Rush Alzheimer’s Neurodisease Center, Rush University Medical Center, 600 South Paulina Street, Chicago, IL 60612 USA
| | - Joe Burrage
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Eilis Hannon
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Gustavo Turecki
- grid.14709.3b0000 0004 1936 8649Douglas Institute, Department of Psychiatry, McGill University, Verdun, QC H4H 1R3 Canada
| | - Zachary Kaminsky
- grid.21107.350000 0001 2171 9311Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD USA ,grid.21107.350000 0001 2171 9311Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA
| | - Jonathan Mill
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Emma L. Dempster
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Therese M. Murphy
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK ,grid.497880.aSchool of Biological and Health Sciences, Technological University Dublin, City Campus, Dublin, 2 Ireland
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23
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Ribosomal DNA transcription in prefrontal pyramidal neurons is decreased in suicide. Eur Arch Psychiatry Clin Neurosci 2020; 270:859-867. [PMID: 30859295 PMCID: PMC7474709 DOI: 10.1007/s00406-019-00996-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 02/22/2019] [Indexed: 02/07/2023]
Abstract
Prefrontal cortical regions, which are crucial for the regulation of emotionally influenced behaviour, play most probably a dominant role in the pathogenesis of suicide. The study was carried out on paraffin-embedded brain tissue blocks containing specimens from the anterior cingulate cortex (dorsal and ventral parts), the orbitofrontal cortex, and the dorsolateral cortex obtained from 23 suicide completers (predominantly violent) with unknown psychiatric diagnosis and 25 non-suicidal controls. The transcriptional activity of ribosomal DNA (rDNA) as a surrogate marker of protein biosynthesis was evaluated separately in layers III and V pyramidal neurons in regions of interest (ROIs) mentioned above by the AgNOR silver staining method bilaterally. The overall statistical analysis revealed a decrease of AgNOR area suggestive of attenuated rDNA activity in suicide victims versus controls, particularly in male subjects. Further ROI-specific post-hoc analyses revealed decreases of the median AgNOR area in suicides compared to non-suicides in all 16 ROIs. However, this effect was only significant in the layer V pyramidal neurons of the right ventral anterior cingulate cortex. Our findings suggest that decreased rDNA transcription in prefrontal pyramidal neurons plays possibly an important role in suicide pathogenesis.
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24
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Abstract
Suicidal behaviors have been associated with both heritable genetic variables and environmental risk factors. Epigenetic processes, such as DNA methylation, have important roles in mediating the effects of the environment on behavior. Dysregulation of these processes has been observed in many psychiatric disorders, and evidence suggests that they may also be involved in suicidal behaviors. Herein, we have summarized candidate gene and epigenome-wide studies which have investigated DNA methylation in relation to suicidal behaviors, as well as discussed some of the limitations of the field to date.
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Affiliation(s)
- Laura M Fiori
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, QC, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, QC, Canada.
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25
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Wikenius E, Moe V, Smith L, Heiervang ER, Berglund A. DNA methylation changes in infants between 6 and 52 weeks. Sci Rep 2019; 9:17587. [PMID: 31772264 PMCID: PMC6879561 DOI: 10.1038/s41598-019-54355-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/14/2019] [Indexed: 12/16/2022] Open
Abstract
Infants undergo extensive developments during their first year of life. Although the biological mechanisms involved are not yet fully understood, changes in the DNA methylation in mammals are believed to play a key role. This study was designed to investigate changes in infant DNA methylation that occurs between 6 and 52 weeks. A total of 214 infant saliva samples from 6 or 52 weeks were assessed using principal component analyses and t-distributed stochastic neighbor-embedding algorithms. Between the two time points, there were clear differences in DNA methylation. To further investigate these findings, paired two-sided student’s t-tests were performed. Differently methylated regions were defined as at least two consecutive probes that showed significant differences, with a q-value < 0.01 and a mean difference > 0.2. After correcting for false discovery rates, changes in the DNA methylation levels were found in 42 genes. Of these, 36 genes showed increased and six decreased DNA methylation. The overall DNA methylation changes indicated decreased gene expression. This was surprising because infants undergo such profound developments during their first year of life. The results were evaluated by taking into consideration the extensive development that occurs during pregnancy. During the first year of life, infants have an overall three-fold increase in weight, while the fetus develops from a single cell into a viable infant in 9 months, with an 875-million-fold increase in weight. It is possible that the findings represent a biological slowing mechanism in response to extensive fetal development. In conclusion, our study provides evidence of DNA methylation changes during the first year of life, representing a possible biological slowing mechanism. We encourage future studies of DNA methylation changes in infants to replicate the findings by using a repeated measures model and less stringent criteria to see if the same genes can be found, as well as investigating whether other genes are involved in development during this period.
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Affiliation(s)
- Ellen Wikenius
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Vibeke Moe
- Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway.,The Center for Child and Adolescent Mental Health, Eastern and Southern Norway (RBUP), Oslo, Norway
| | - Lars Smith
- Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway
| | - Einar R Heiervang
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Oslo University Hospital, Oslo, Norway
| | - Anders Berglund
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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26
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Gaine ME, Seifuddin F, Sabunciyan S, Lee RS, Benke KS, Monson ET, Zandi PP, Potash JB, Willour VL. Differentially methylated regions in bipolar disorder and suicide. Am J Med Genet B Neuropsychiatr Genet 2019; 180:496-507. [PMID: 31350827 PMCID: PMC8375453 DOI: 10.1002/ajmg.b.32754] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/24/2019] [Accepted: 07/15/2019] [Indexed: 12/29/2022]
Abstract
The addition of a methyl group to, typically, a cytosine-guanine dinucleotide (CpG) creates distinct DNA methylation patterns across the genome that can regulate gene expression. Aberrant DNA methylation of CpG sites has been associated with many psychiatric disorders including bipolar disorder (BD) and suicide. Using the SureSelectXT system, Methyl-Seq, we investigated the DNA methylation status of CpG sites throughout the genome in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls. We identified differentially methylated regions (DMRs) from three analyses: (a) BD subjects compared to nonpsychiatric controls (BD-NC), (b) BD subjects who died by suicide compared to nonpsychiatric controls (BDS-NC), and (c) BDS subjects compared to BD subjects who died from other causes (BDS-BDNS). One DMR from the BDS-NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects. This finding remained significant after multiple testing (PBootstrapped = 9.0 × 10-3 ), was validated using pyrosequencing, and was more significant in males. A secondary analysis utilized Ingenuity Pathway Analysis to identify enrichment in nominally significant DMRs. This identified an association with several pathways including axonal guidance signaling, calcium signaling, β-adrenergic signaling, and opioid signaling. Our comprehensive study provides further support that DNA methylation alterations influence the risk for BD and suicide. However, further investigation is required to confirm these associations and identify their functional consequences.
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Affiliation(s)
- Marie E. Gaine
- Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Fayaz Seifuddin
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Sarven Sabunciyan
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland,Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Richard S. Lee
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Kelly S. Benke
- Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Eric T. Monson
- Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Peter P. Zandi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland,Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - James B. Potash
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Virginia L. Willour
- Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa
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27
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Mustafin RN, Kazantseva AV, Enikeeva RF, Davydova YD, Malykh SB, Viktorov VV, Khusnutdinova EK. Epigenetics of suicidal behavior. Vavilovskii Zhurnal Genet Selektsii 2019. [DOI: 10.18699/vj19.531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Suicide is the second leading cause of death among young people and therefore being a serious global problem worldwide. The study of genetic and epigenetic factors in the development of suicidal behavior plays an important role in the development of advanced methods of diagnosis and treatment of this pathology. The role of hereditary factors in the development of suicidal behavior is estimated at 30–55 %, with a pronounced comorbidity with other psychopathologies. The study of genetic liability to suicidal behavior is based on molecular-genetic methods including association and linkage analyses, chip gene expression arrays, and genome-wide association studies. Published data identified multiple genes including those involved in the functioning of serotonergic (SLC6A4, TPH, 5-HT1A), hypothalamic-pituitary-adrenal systems (FKBP5) and polyamines (SAT and OATL1) associated with suicidal behavior. However, the diversity of interacting genetic loci complicates the interpretation of the development of a complex phenotype of pathology and prevents the association from being detected. To solve this problem and interpret the missing relationship between the environment and the genome, promising results were obtained from a study of epigenetic factors, which affected the expression of a number of candidate genes involved in brain functioning in suicidal behavior. The analysis of a brain obtained from suicide victims, representing a unique tool for the analysis of modified genomic processes, revealed a wide range of reprogramming patterns of DNA methylation in promoters of the genes of polyamine (OAZ1, OAZ2, AMD1, ARG2, SKA2), serotonergic (SLC6A4) and GABAergic (GABRA1) systems, HPA-axis (GR, NR3C1), tyrosine kinase (TrkB) receptors, brain-derived neurotrophic factor (BDNF). The role of histone modifications in distinct genes (Cx30, Cx43, TrkB.T1) and the expression of specific long noncoding RNAs and microRNAs in the development of suicidal behavior, which is promising for the development of diagnostic algorithms and target therapy, is discussed.
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Affiliation(s)
- R. N. Mustafin
- Bashkir State Medical University;
Bashkir State University
| | - A. V. Kazantseva
- Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
| | - R. F. Enikeeva
- Bashkir State University;
Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
| | - Yu. D. Davydova
- Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
| | - S. B. Malykh
- Psychological Institute of the Russian Academy of Education
| | | | - E. K. Khusnutdinova
- Bashkir State Medical University;
Bashkir State University;
Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
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28
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González-Castro TB, Tovilla-Zárate CA, Genis-Mendoza AD, Juárez-Rojop IE, Nicolini H, López-Narváez ML, Martínez-Magaña JJ. Identification of gene ontology and pathways implicated in suicide behavior: Systematic review and enrichment analysis of GWAS studies. Am J Med Genet B Neuropsychiatr Genet 2019; 180:320-329. [PMID: 31045331 DOI: 10.1002/ajmg.b.32731] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 04/03/2019] [Accepted: 04/16/2019] [Indexed: 12/14/2022]
Abstract
Multiple large-scale studies such as genome-wide association studies (GWAS) have been performed to identify genetic contributors to suicidal behaviors (SB). We aimed to summarize and analyze the information obtained in SB GWAS, to explore the biological process gene ontology (GO) of genes associated with SB from GWAS, and to determine the possible implications of the genes associated with SB in Kyoto encyclopedias of genes and genomes (KEGG) biological pathways. The articles included in the analysis were obtained from PubMed and Scopus databases. Enrichment analyses were performed in Enrichr to evaluate the KEGG pathways and GO of the genes associated with SB of GWAS. The findings of biological process GO analysis showed 924 GO involved in genes related with SB; of those, the regulation of glucose import in response to insulin stimulus, regulation of protein localization to plasma membrane, positive regulation of endopeptidase activity, heterotypic cell-cell adhesion, regulation of cardiac muscle cell contraction, positive regulation of protein localization to plasma membrane, and positive regulation of protein localization to cell periphery biological process GO showed significant statistical association. Furthermore, we obtained 130 KEGG pathways involved in genes related with SB, which Aldosterone synthesis and secretion, Rap1 signaling pathway and arrhythmogenic right ventricular cardiomyopathy pathways showed a significant statistical association. These findings give a better perspective of the biological participation of genes associated with SB, which will be important to perform adequate strategies to prevent and treat SB.
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Affiliation(s)
- Thelma B González-Castro
- Multidisciplinary Academic Division of Jalpa de Méndez, Juárez Autonomous University of Tabasco, Jalpa de Méndez, Tabasco, Mexico.,Multidisciplinary Academic Division of Health Sciences, Juárez Autonomous University of Tabasco, Villahermosa, Tabasco, Mexico
| | - Carlos A Tovilla-Zárate
- Multidisciplinary Academic Division of Comalcalco, Juárez Autonomous University of Tabasco, Comalcalco, Tabasco, Mexico
| | - Alma D Genis-Mendoza
- Secretary of Health, National Institute of Genomic Medicine (INMEGEN), City of Mexico, Mexico.,Secretary of Health, Children's Psychiatric Hospital "Dr. Juan N. Navarro", City of Mexico, Mexico
| | - Isela E Juárez-Rojop
- Multidisciplinary Academic Division of Comalcalco, Juárez Autonomous University of Tabasco, Comalcalco, Tabasco, Mexico
| | - Humberto Nicolini
- Secretary of Health, National Institute of Genomic Medicine (INMEGEN), City of Mexico, Mexico.,Secretary of Health, Children's Psychiatric Hospital "Dr. Juan N. Navarro", City of Mexico, Mexico
| | | | - José J Martínez-Magaña
- Secretary of Health, National Institute of Genomic Medicine (INMEGEN), City of Mexico, Mexico
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29
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Kouter K, Zupanc T, Videtič Paska A. Genome-wide DNA methylation in suicide victims revealing impact on gene expression. J Affect Disord 2019; 253:419-425. [PMID: 31103807 DOI: 10.1016/j.jad.2019.04.077] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 04/10/2019] [Accepted: 04/17/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Suicidal behavior is a multifactorial, polygenic state that affects millions worldwide. It is a result of interplay between hereditary and environmental factors, tied together by epigenetics. Despite vast knowledge on suicidality complete mechanism and factors leading to suicide are unknown. However there is an indication between changes in DNA methylation patterns and suicidal behavior. METHODS To identify differential methylation we formed a homogenous group of male suicide victims who died by hanging and control group. Altogether our study included 18 subjects in which two brain regions, Brodmann area 9 (9 suicide victims and 9 controls)) and hippocampus (6 suicide victims and 6 controls) were investigated using next-generation sequencing (NGS). RESULTS Our results have shown several differences in methylation level between suicide victims and controls in both brain regions (>25% difference in methylation and q-value < 0.01), with gene ontology pointing towards cell structural integrity and nervous system regulation. Additional gene expression analysis identified changes in two genes, ZNF714 (p-value = 0.002) and NRIP3 (p-value = 0.046). LIMITATIONS Major limitation is small sample size. Our analysis was conducted on brain tissue including different cell types so the results are a representation of a methylation pattern for the whole brain tissue sample. CONCLUSIONS We performed a preliminary methylation study with single base pair resolution using NGS on one of the world populations with a very high suicide risk. Obtained results offer novel insights into altered methylation patterns in suicide victims, which could provide a starting point for further studies on clinical samples with highly expressed suicide risk.
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Affiliation(s)
- Katarina Kouter
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia
| | - Tomaž Zupanc
- Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, Korytkova ulica 2, SI-1000 Ljubljana, Slovenia
| | - Alja Videtič Paska
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
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30
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Zhou Y, Lutz P, Ibrahim EC, Courtet P, Tzavara E, Turecki G, Belzeaux R. Suicide and suicide behaviors: A review of transcriptomics and multiomics studies in psychiatric disorders. J Neurosci Res 2018; 98:601-615. [DOI: 10.1002/jnr.24367] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 11/23/2018] [Accepted: 11/26/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Yi Zhou
- McGill Group for Suicide Studies Douglas Mental Health University Institute, McGill University Montréal Canada
| | - Pierre‐Eric Lutz
- Centre National de la Recherche Scientifique Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 Strasbourg France
| | - El Chérif Ibrahim
- Institut de Neurosciences de la Timone ‐ UMR7289,CNRS Aix‐Marseille Université Marseille France
- Fondamental, Fondation de Recherche et de Soins en Santé Mentale Créteil France
| | - Philippe Courtet
- Fondamental, Fondation de Recherche et de Soins en Santé Mentale Créteil France
- CHRU Montpellier, University of Montpellier, INSERM unit 1061 Montpellier France
| | - Eleni Tzavara
- Fondamental, Fondation de Recherche et de Soins en Santé Mentale Créteil France
- INSERM, UMRS 1130, CNRS, UMR 8246, Sorbonne University UPMC, Neuroscience Paris‐Seine Paris France
| | - Gustavo Turecki
- McGill Group for Suicide Studies Douglas Mental Health University Institute, McGill University Montréal Canada
| | - Raoul Belzeaux
- Institut de Neurosciences de la Timone ‐ UMR7289,CNRS Aix‐Marseille Université Marseille France
- Fondamental, Fondation de Recherche et de Soins en Santé Mentale Créteil France
- AP‐HM, Pôle de Psychiatrie Marseille France
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31
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Bani-Fatemi A, Jeremian R, Wang KZ, Silveira J, Zai C, Kolla NJ, Graff A, Gerretsen P, Strauss J, De Luca V. Epigenome-wide association study of suicide attempt in schizophrenia. J Psychiatr Res 2018; 104:192-197. [PMID: 30103066 DOI: 10.1016/j.jpsychires.2018.07.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 06/23/2018] [Accepted: 07/18/2018] [Indexed: 01/01/2023]
Abstract
Schizophrenia is a major clinical problem and represents a major risk factor for suicide. The molecular mechanisms of suicidal behavior in psychosis remain poorly investigated, although it has been hypothesized that epigenetic processes are involved in the etiology of both psychosis and suicidality. In this study, epigenome-wide patterns of methylation were measured in schizophrenia suicide attempters (n = 54) and schizophrenia non-suicide attempters (n = 69) using DNA extracted from white blood cells (WBC). Analyses focused on identifying differentially methylated CpG sites and gene regions between the attempters and non-attempters. We identified the CpG site cg19647197 within the CCDC53 gene, which is characterized by hypomethylation of WBC in the attempters compared to the non-attempters. Our results suggest that there is variation in DNA methylation associated with suicide attempt that may offer novel highlights into the molecular mechanisms linked to suicide attempt associated with schizophrenia.
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Affiliation(s)
| | | | - Kevin Z Wang
- Centre for Addiction and Mental Health, Toronto, Canada
| | | | - Clement Zai
- Centre for Addiction and Mental Health, Toronto, Canada
| | | | - Ariel Graff
- Centre for Addiction and Mental Health, Toronto, Canada
| | | | - John Strauss
- Centre for Addiction and Mental Health, Toronto, Canada
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32
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Sonal A, Raghavan V. Brain derived neurotrophic factor (BDNF) and suicidal behavior: A review of studies from Asian countries. Asian J Psychiatr 2018. [PMID: 29525506 DOI: 10.1016/j.ajp.2018.03.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The biological basis of suicide and suicidal behavior is actively researched. Recently, the role of Brain Derived Neurotropic Factor (BDNF) in suicidal behavior has gained attention and significant results are observed. In this review, we aimed to focus on the studies from Asian countries that have explored the role of BDNF and suicidal behavior. The review highlights the findings from these studies and discusses the possible avenues that should be explored in future studies from Asian countries to understand more on suicidal behavior and possible prevention.
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Affiliation(s)
- Akanksha Sonal
- Department of Geriatric Psychiatry, King George Medical University, Lucknow, Uttar Pradesh, India
| | - Vijaya Raghavan
- Schizophrenia Research Foundation, R/7A, North Main Road, Anna Nagar West Extension, Chennai, Tamil Nadu, 600101, India.
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33
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Lutz PE, Mechawar N, Turecki G. Neuropathology of suicide: recent findings and future directions. Mol Psychiatry 2017; 22:1395-1412. [PMID: 28696430 DOI: 10.1038/mp.2017.141] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 05/21/2017] [Accepted: 05/26/2017] [Indexed: 12/11/2022]
Abstract
Suicide is a major public health concern and a leading cause of death in most societies. Suicidal behaviour is complex and heterogeneous, likely resulting from several causes. It associates with multiple factors, including psychopathology, personality traits, early-life adversity and stressful life events, among others. Over the past decades, studies in fields ranging from neuroanatomy, genetics and molecular psychiatry have led to a model whereby behavioural dysregulation, including suicidal behaviour (SB), develops as a function of biological adaptations in key brain systems. More recently, the unravelling of the unique epigenetic processes that occur in the brain has opened promising avenues in suicide research. The present review explores the various facets of the current knowledge on suicidality and discusses how the rapidly evolving field of neurobehavioural epigenetics may fuel our ability to understand, and potentially prevent, SB.
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Affiliation(s)
- P-E Lutz
- McGill Group for Suicide Studies, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada
| | - N Mechawar
- McGill Group for Suicide Studies, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada.,Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada
| | - G Turecki
- McGill Group for Suicide Studies, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada.,Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada
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34
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Mahar I, Alosco ML, McKee AC. Psychiatric phenotypes in chronic traumatic encephalopathy. Neurosci Biobehav Rev 2017; 83:622-630. [PMID: 28888534 DOI: 10.1016/j.neubiorev.2017.08.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 08/12/2017] [Accepted: 08/30/2017] [Indexed: 12/14/2022]
Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder involving cognitive, motor, and psychiatrically-relevant symptoms resulting from repetitive head impacts. Psychiatric phenotypes of CTE, including depression and suicidality, present particular challenges for CTE research, given that the diagnosis requires postmortem neuropathological examination. The pathognomonic lesion of CTE is the perivascular accumulation of hyperphosphorylated tau (ptau) protein at the depths of cortical sulci. These lesions are found in the earliest disease stages, and with advancing pathological severity, ptau deposition occurs in widespread brain regions in a four-stage scheme of severity. We review the psychiatric phenotypes of individuals neuropathologically diagnosed with CTE, and suggest that earlier CTE stages hold particular interest for psychiatric CTE research. In the early CTE stages, there is ptau pathology in frontal cortex and axonal loss in the frontal white matter, followed by progressive ptau neurofibrillary degeneration in the amygdala and hippocampus. Neuropathological changes in the frontal and medial temporal lobes may underlie psychiatric phenotypes. Additional insight into the association between CTE pathology and psychiatric sequelae may come from advancements in in vivo methods of CTE detection. Further epidemiological, clinical, and postmortem studies are needed to validate the nature of psychiatric sequelae in CTE.
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Affiliation(s)
- Ian Mahar
- Dept. of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA, USA
| | - Michael L Alosco
- Dept. of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA, USA
| | - Ann C McKee
- Dept. of Neurology, Boston University School of Medicine, Boston, MA, USA; Dept. of Pathology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and Chronic Traumatic Encephalopathy Center, Boston University School of Medicine, Boston, MA, USA; Department of Pathology and Laboratory Medicine, VA Boston Healthcare System, Boston, MA, USA.
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35
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Recent Progress in Functional Genomic Studies of Depression and Suicide. CURRENT GENETIC MEDICINE REPORTS 2017. [DOI: 10.1007/s40142-017-0112-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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36
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van der Laan S, Salvetat N, Weissmann D, Molina F. Emerging RNA editing biomarkers will foster drug development. Drug Discov Today 2017; 22:1056-1063. [PMID: 28188894 DOI: 10.1016/j.drudis.2017.01.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 12/19/2016] [Accepted: 01/30/2017] [Indexed: 01/02/2023]
Abstract
Unanticipated adverse drug reactions (ADRs) on the central nervous system are a major cause of clinical attrition and market withdrawal. Current practices for their prospective assessment still lean on extensive analysis of rodent behaviour despite their highly controversial predictive value. Human-derived in vitro models that objectively quantify mechanism-related biomarkers can greatly contribute to better ADR prediction at early developmental stages. Adenosine-to-inosine RNA editing constitutes a physiological cellular process that translates environmental cues by regulating protein function at the synaptic level in health and disease. Robust solutions based on NGS-based quantification of RNA editing biomarkers have emerged to predict the likelihood of treatment-related suicidal ideation and behaviour allowing cost-effective high-throughput drug screening as a strategy for risk mitigation.
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Affiliation(s)
- Siem van der Laan
- Sys2Diag FRE3690 CNRS/ALCEDIAG, Complex System Modeling and Engineering for Diagnosis, Cap delta/Parc Euromédecine, 1682 rue de la Valsière CS 61003, 34184 Montpellier Cedex 4, France.
| | - Nicolas Salvetat
- Sys2Diag FRE3690 CNRS/ALCEDIAG, Complex System Modeling and Engineering for Diagnosis, Cap delta/Parc Euromédecine, 1682 rue de la Valsière CS 61003, 34184 Montpellier Cedex 4, France
| | - Dinah Weissmann
- Sys2Diag FRE3690 CNRS/ALCEDIAG, Complex System Modeling and Engineering for Diagnosis, Cap delta/Parc Euromédecine, 1682 rue de la Valsière CS 61003, 34184 Montpellier Cedex 4, France
| | - Franck Molina
- Sys2Diag FRE3690 CNRS/ALCEDIAG, Complex System Modeling and Engineering for Diagnosis, Cap delta/Parc Euromédecine, 1682 rue de la Valsière CS 61003, 34184 Montpellier Cedex 4, France.
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Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide. Transl Psychiatry 2017; 7:e989. [PMID: 28045465 PMCID: PMC5545719 DOI: 10.1038/tp.2016.249] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 10/16/2016] [Indexed: 02/06/2023] Open
Abstract
Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.
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38
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An integrative review of methylation at the serotonin transporter gene and its dialogue with environmental risk factors, psychopathology and 5-HTTLPR. Neurosci Biobehav Rev 2016; 72:190-209. [PMID: 27880876 DOI: 10.1016/j.neubiorev.2016.11.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 11/04/2016] [Accepted: 11/06/2016] [Indexed: 11/24/2022]
Abstract
Gene-environment (G×E) interactions have largely been regarded as the root of many complex disorders, including several psychiatric disorders. In this regard, it has been hypothesized that epigenetic mechanisms may be the main mediators of such interactions. Of particular interest is the previously described interaction between psychosocial stress and genetic variability of the serotonin transporter gene (SLC6A4) in its polymorphic region 5-HTTLPR. Here we review the literature concerning SLC6A4 methylation in association with environmental, clinical or genetic variables. While SLC6A4 hypermethylation has typically been described to be independently associated with both early life stress and depressive disorders, only a few papers address whether methylation could mediate the interaction between stress and 5-HTTLPR in predicting psychopathological risk. Nevertheless, research preliminarily indicates a methylation-driven increased vulnerability of carriers of the short allele of 5-HTTLPR to psychiatric disorders when exposed to early stress or soon after exposure to stress.
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