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Tesli M, Nesvåg R, Haukvik UK, Gustavson K, Tesli N, Friestad C, Skardhamar T, Naess Ø, Czajkowski N, Kendler KS, Reichborn-Kjennerud T, Ystrom E. Common genetic and environmental risk for personality disorders and psychotic-like experiences in young adult twins. Acta Psychiatr Scand 2023; 148:561-569. [PMID: 37497694 DOI: 10.1111/acps.13596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 07/11/2023] [Accepted: 07/15/2023] [Indexed: 07/28/2023]
Abstract
INTRODUCTION Psychotic-like experiences (PLE) have been associated with the subsequent emergence of psychotic disorders as well as several other domains of psychopathology. In this twin study, we estimated the genetic and environmental correlations between PLE and 10 personality disorders (PD). METHODS Diagnoses of 10 PDs according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and PLE from the Composite International Diagnostic Interview (CIDI) were retrieved for 2793 young adult twins from the Norwegian Twin Registry. Risk for having a PD and PLEs was modeled using item response theory. Biometric twin models were fitted to estimate the genetic and environmental correlations between PDs and PLEs. Co-twin control analysis was performed to estimate additional within-family risk for PLEs when having a PD. RESULTS Phenotypic overlap between PDs and PLEs ranged from 14% to 44% in males and from 11% to 39% in females, with the highest overlap for borderline PD in both sexes. In general, we found higher genetic correlations (r = 0.14-0.72) than environmental correlations (r = 0.06-0.28) between PDs and PLEs. The highest genetic correlations between PLE and PDs were found for borderline (r = 0.72), paranoid (r = 0.56), schizotypal (r = 0.56) and antisocial PD (r = 0.49). CONCLUSION We found that the co-occurrence between PDs and PLE is the best explained by shared genetic determinants, with minor contributions from environmental factors. Interestingly, borderline PD was highly genetically correlated with PLE, warranting molecular genetic studies of this association.
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Affiliation(s)
- Martin Tesli
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Centre for Research and Education in Forensic Psychiatry, Department of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Ragnar Nesvåg
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
| | - Unn K Haukvik
- Centre for Research and Education in Forensic Psychiatry, Department of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kristin Gustavson
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Natalia Tesli
- Centre for Research and Education in Forensic Psychiatry, Department of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Christine Friestad
- Centre for Research and Education in Forensic Psychiatry, Department of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- University College of Norwegian Correctional Service, Lillestrøm, Norway
| | - Torbjørn Skardhamar
- Department of Sociology and Human Geography, University of Oslo, Oslo, Norway
| | - Øyvind Naess
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Department of Community Medicine and Global Health, Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Nikolai Czajkowski
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Kenneth S Kendler
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Ted Reichborn-Kjennerud
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Eivind Ystrom
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
- PharmacoEpidemiology and Drug Safety Research Group, School of Pharmacy, University of Oslo, Oslo, Norway
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Dash GF, Gizer IR, Martin NG, Slutske WS. Specificity in genetic and environmental risk for prescription opioid misuse and heroin use. Psychol Med 2023; 53:6828-6837. [PMID: 36946318 PMCID: PMC10514228 DOI: 10.1017/s003329172300034x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/23/2023] [Accepted: 02/01/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND Many studies aggregate prescription opioid misuse (POM) and heroin use into a single phenotype, but emerging evidence suggests that their genetic and environmental influences may be partially distinct. METHODS In total, 7164 individual twins (84.12% complete pairs; 59.81% female; mean age = 30.58 years) from the Australian Twin Registry reported their lifetime misuse of prescription opioids, stimulants, and sedatives, and lifetime use of heroin, cannabis, cocaine/crack, illicit stimulants, hallucinogens, inhalants, solvents, and dissociatives via telephone interview. Independent pathway models (IPMs) and common pathway models (CPMs) partitioned the variance of drug use phenotypes into general and drug-specific genetic (a), common environmental (c), and unique environmental factors (e). RESULTS An IPM with one general a and one general e factor and a one-factor CPM provided comparable fit to the data. General factors accounted for 55% (a = 14%, e = 41%) and 79% (a = 64%, e = 15%) of the respective variation in POM and heroin use in the IPM, and 25% (a = 12%, c = 8%, e = 5%) and 80% (a = 38%, c = 27%, e = 15%) of the respective variation in POM and heroin use in the CPM. Across both models, POM emerged with substantial drug-specific genetic influence (26-39% of total phenotypic variance; 69-74% of genetic variance); heroin use did not (0% of total phenotypic variance; 0% of genetic variance in both models). Prescription sedative misuse also demonstrated significant drug-specific genetic variance. CONCLUSIONS Genetic variation in POM, but not heroin use, is predominantly drug-specific. Misuse of prescription medications that reduce experiences of subjective distress may be partially influenced by sources of genetic variation separate from illicit drug use.
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Affiliation(s)
- Genevieve F. Dash
- Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA
| | - Ian R. Gizer
- Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA
| | | | - Wendy S. Slutske
- Department of Family Medicine and Community Health and Center for Tobacco Research and Intervention, University of Wisconsin, Madison, WI 53711, USA
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Dash GF, Martin NG, Agrawal A, Lynskey MT, Slutske WS. Are prescription misuse and illicit drug use etiologically distinct? A genetically-informed analysis of opioids and stimulants. Psychol Med 2022; 52:3176-3183. [PMID: 33455586 PMCID: PMC8286273 DOI: 10.1017/s0033291720005267] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue. METHODS A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types. RESULTS Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use. CONCLUSIONS Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.
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Affiliation(s)
- Genevieve F. Dash
- Department of Psychological Sciences, University of Missouri, Columbia, MO, USA
| | - Nicholas G. Martin
- Queensland Institute of Medical Research- Berghofer, Brisbane, QLD, Australia
| | - Arpana Agrawal
- School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Michael T. Lynskey
- Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Wendy S. Slutske
- Department of Psychological Sciences, University of Missouri, Columbia, MO, USA
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4
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Philyaw TJ, Rothenfluh A, Titos I. The Use of Drosophila to Understand Psychostimulant Responses. Biomedicines 2022; 10:119. [PMID: 35052798 PMCID: PMC8773124 DOI: 10.3390/biomedicines10010119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 01/27/2023] Open
Abstract
The addictive properties of psychostimulants such as cocaine, amphetamine, methamphetamine, and methylphenidate are based on their ability to increase dopaminergic neurotransmission in the reward system. While cocaine and methamphetamine are predominately used recreationally, amphetamine and methylphenidate also work as effective therapeutics to treat symptoms of disorders including attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Although both the addictive properties of psychostimulant drugs and their therapeutic efficacy are influenced by genetic variation, very few genes that regulate these processes in humans have been identified. This is largely due to population heterogeneity which entails a requirement for large samples. Drosophila melanogaster exhibits similar psychostimulant responses to humans, a high degree of gene conservation, and allow performance of behavioral assays in a large population. Additionally, amphetamine and methylphenidate reduce impairments in fly models of ADHD-like behavior. Therefore, Drosophila represents an ideal translational model organism to tackle the genetic components underlying the effects of psychostimulants. Here, we break down the many assays that reliably quantify the effects of cocaine, amphetamine, methamphetamine, and methylphenidate in Drosophila. We also discuss how Drosophila is an efficient and cost-effective model organism for identifying novel candidate genes and molecular mechanisms involved in the behavioral responses to psychostimulant drugs.
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Affiliation(s)
- Travis James Philyaw
- Molecular Biology Graduate Program, University of Utah, Salt Lake City, UT 84112, USA;
| | - Adrian Rothenfluh
- Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT 84108, USA
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
- Department of Neurobiology, University of Utah, Salt Lake City, UT 84132, USA
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Iris Titos
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
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Fernàndez-Castillo N, Cabana-Domínguez J, Corominas R, Cormand B. Molecular genetics of cocaine use disorders in humans. Mol Psychiatry 2022; 27:624-639. [PMID: 34453125 PMCID: PMC8960411 DOI: 10.1038/s41380-021-01256-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 07/01/2021] [Accepted: 07/30/2021] [Indexed: 12/11/2022]
Abstract
Drug addiction, one of the major health problems worldwide, is characterized by the loss of control in drug intake, craving, and withdrawal. At the individual level, drugs of abuse produce serious consequences on health and have a negative impact on the family environment and on interpersonal and work relationships. At a wider scale, they have significant socio-economic and public health consequences and they cause delinquency and citizen insecurity. Cocaine, a psychostimulant substance, is one of the most used illicit drugs, especially in America, Western Europe, and Australia. Cocaine use disorders (CUD) are complex multifactorial conditions driven by both genetic and environmental influences. Importantly, not all people who use cocaine develop CUD, and this is due, at least in part, to biological factors that are encoded in the genome of individuals. Acute and repeated use of cocaine induces epigenetic and gene expression changes responsible for the neuronal adaptations and the remodeling of brain circuits that lead to the transition from use to abuse or dependence. The purpose of this review is to delineate such factors, which should eventually help to understand the inter-individual variability in the susceptibility to cocaine addiction. Heritability estimates for CUD are high and genetic risk factors for cocaine addiction have been investigated by candidate gene association studies (CGAS) and genome-wide association studies (GWAS), reviewed here. Also, the high comorbidity that exists between CUD and several other psychiatric disorders is well known and includes phenotypes like schizophrenia, aggression, antisocial or risk-taking behaviors. Such comorbidities are associated with a worse lifetime trajectory, and here we report shared genetic factors that may contribute to them. Gene expression changes and epigenetic modifications induced by cocaine use and chronic abuse in humans are addressed by reviewing transcriptomic studies performed on neuronal cells and on postmortem brains. We report some genes which expression is altered by cocaine that also bear genetic risk variants for the disorder. Finally, we have a glance to the pharmacogenetics of CUD treatments, still in early stages. A better understanding of the genetic underpinnings of CUD will foster the search of effective treatments and help to move forward to personalized medicine.
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Affiliation(s)
- Noèlia Fernàndez-Castillo
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. .,Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain. .,Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain.
| | - Judit Cabana-Domínguez
- grid.5841.80000 0004 1937 0247Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia Spain ,grid.452372.50000 0004 1791 1185Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain ,grid.5841.80000 0004 1937 0247Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia Spain ,grid.411160.30000 0001 0663 8628Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia Spain
| | - Roser Corominas
- grid.5841.80000 0004 1937 0247Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia Spain ,grid.452372.50000 0004 1791 1185Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain ,grid.5841.80000 0004 1937 0247Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia Spain ,grid.411160.30000 0001 0663 8628Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia Spain
| | - Bru Cormand
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. .,Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain. .,Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain.
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Anker E, Haavik J, Heir T. Alcohol and drug use disorders in adult attention-deficit/hyperactivity disorder: Prevalence and associations with attention-deficit/hyperactivity disorder symptom severity and emotional dysregulation. World J Psychiatry 2020; 10:202-211. [PMID: 33014721 PMCID: PMC7515748 DOI: 10.5498/wjp.v10.i9.202] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/11/2020] [Accepted: 08/15/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND High risk of alcohol and drug use disorders in people with attention-deficit/hyperactivity disorder (ADHD) calls for exploratory research of relationships with clinical features of ADHD. AIM To estimate prevalence of alcohol/drug use disorders and associations with ADHD symptom severity and emotional dysregulation, in adults with ADHD. METHODS This observational cross-sectional clinical study consisted of patients admitted to a private psychiatric outpatient clinic in Oslo, Norway (2014-2018). Five-hundred and fifty-eight eligible patients diagnosed with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) agreed to participate. Alcohol and drug use disorders were diagnosed using the Mini International Neuropsychiatric Interview (MINI). Dependence and abuse were merged into "use" disorder as in MINI version 7.0/DSM-5. Questions were related both to lifetime and the past 12-mo. ADHD severity was assessed by the Adult ADHD Self Report Scale (ASRS). Subdivisions of the ASRS questionnaire as inattentive items and hyperactive/impulsivity items were recorded separately. Emotional dysregulation was assessed by the eight-item version of Barkley's Current Behavior Scale - Self Report. RESULTS The 12-mo prevalence was 5.3% for alcohol use disorder and 13.7% for drug use disorder. The lifetime prevalence was 12.0% for alcohol use disorder and 27.7% for drug use disorder. Men had higher rates of both alcohol use disorder and drug use disorder compared to women. The prevalence of drug use disorder was more than twice that of alcohol use disorder for both sexes. The drugs most participants reported having used were (in descending order): Amphetamine (19.1%), cannabis (17.1%), cocaine or ecstasy (7.4%), benzodiazepines (7.4%), and heroin or other opioids (2.9%). Lifetime drug use disorder was significantly associated with both hyperactivity-impulsivity symptoms and emotional dysregulation symptom severity. Lifetime alcohol use disorder, on the other hand, was not significantly associated with ADHD symptoms or emotional dysregulation when adjusted for gender and age. CONCLUSION Patients with ADHD have a high lifetime prevalence of drug use disorder, which is associated with higher levels of hyperactivity-impulsivity symptoms and emotional dysregulation.
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Affiliation(s)
| | - Jan Haavik
- Department of Biomedicine, University of Bergen, Bergen 5007, Norway
- Division of Psychiatry, Haukeland University Hospital, Bergen 5021, Norway
| | - Trond Heir
- Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
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Wiig EM, Halsa A, Bramness J, Myra SM, Haugland BSM. Rescue the child or treat the adult? Understandings among professionals in dual treatment of substance-use disorders and parenting. NORDIC STUDIES ON ALCOHOL AND DRUGS 2018; 35:179-195. [PMID: 32934526 PMCID: PMC7434155 DOI: 10.1177/1455072518773615] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 04/04/2018] [Indexed: 11/16/2022] Open
Abstract
Aims: Dual treatment of parents with substance-use disorders (SUD) is an approach which aims to meet the needs of both SUD patients and their children. Whereas the parents need to learn to live without substances, the children need a predictable and structured environment with parents who are sensitive and psychologically available. In this study we explore the possibilities and challenges of this joint approach from the perspectives of professionals employed in an in-patient facility for families with parental SUD. Methods: A qualitative design was used comprising three focus-group interviews with 15 professionals: two groups with ward staff and one with therapists, all working at a family ward for parents with SUD and their children. Data were analysed using thematic analysis. Results: Professionals faced difficulties combining the needs of parents and children and seemed to choose to prioritise either the adult with SUD or the wellbeing of the child. However, some professionals described what might be a third and alternative solution by supporting the mothers in everyday life, routines, and care, through exploring present moment situations. This approach seemed to help parents become more conscious of the child, their interaction with the child, and their own feelings. Professionals described working at the family ward as emotionally challenging. Conclusion: Combining treatment of parental SUD, interventions to improve parenting roles and practice, and at the same time focusing on the developmental needs of children, is experienced as a complex and demanding task. Different priorities and treatment aims may enhance tensions between professionals. Even though professionals experience in-patient dual treatment as challenging, they believe this approach facilitates positive development in substance dependent parents and their children.
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Affiliation(s)
- Eli Marie Wiig
- Universitetet i Oslo Det medisinske fakultet, Oslo, Norway
| | | | - Jørgen Bramness
- ROP Nasjonal kompetansetjeneste for samtidig rus- og psykisk lidelse, Sykehuset Innlandet HF, Divisjon Psykisk Helsevern, Brumunddal, Norway
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Waaktaar T, Kan KJ, Torgersen S. The genetic and environmental architecture of substance use development from early adolescence into young adulthood: a longitudinal twin study of comorbidity of alcohol, tobacco and illicit drug use. Addiction 2018; 113:740-748. [PMID: 29057620 DOI: 10.1111/add.14076] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 01/26/2017] [Accepted: 10/13/2017] [Indexed: 02/02/2023]
Abstract
AIMS To investigate how use of alcohol, illicit drugs and tobacco come from substance-specific pathways and from pathways general to all three substances through adolescent development. DESIGN Analysis of population-based survey. Adolescent twins reported alcohol use (AU), tobacco use (TU) and illicit drug use (IDU) in three waves (2006, 2008, 2010). Restructuring data by age allowed for variance decomposition into age- and substance-specific and common genetic and environmental variance components. SETTING Norway. PARTICIPANTS Seven national twin birth cohorts from 1988 to 1994, totalling 1483 pairs (558 monozygotic; 925 dizygotic, same and opposite sex). MEASUREMENTS Six-point Likert scores of AU, TU and IDU on items from the Monitoring the Future Study. FINDINGS Substance use was found to be highly heritable; a2 = 0.73 [95% confidence interval (CI) = 0.61-0.94] for AU, a2 = 0.36 (CI = 0.18-0.52); d2 = 0.49 (95% CI = 0.29-0.62) for IDU and a2 = 0.46 (95% CI = 0.23-0.54); d2 = 0.05 (95% CI = 0.00-0.07) for TU during the whole adolescence period. General substance use (GSU) was also highly heritable at each age and averaged a2 = 0.57 (95% CI = 0.48-0.66). There was a high genetic carry-over from earlier age to later age. Genetic effects on GSU at ages 12-14 years were still detectable 4 years later. New substance (general and specific)-genetic effects also appeared. IDU demonstrated significant non-additive genetic effects (ages 12-14 years). Shared environment had a small impact on AU only. There was almost no non-shared environmental carry-over from age to age, the effect probably due partly to reliability deficiency. Common genetic effects among substance and substance-specific genetic effects were observed at each age-period. CONCLUSIONS Among Norwegian adolescents, there appear to be strong genetic effects on both substance-specific and comorbid use of alcohol, illicit drugs and tobacco; individual differences in alcohol use can be explained partially by family background.
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Affiliation(s)
- Trine Waaktaar
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Kees-Jan Kan
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.,Research Institute of Child Development and Education, Amsterdam, the Netherlands
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Abstract
Drug addiction involves long-term behavioral abnormalities that arise in response to repeated exposure to drugs of abuse in vulnerable individuals. It is a multifactorial syndrome involving a complex interplay between genes and the environment. Evidence suggests that the underlying mechanisms regulating these persistent behavioral abnormalities involve changes in gene expression throughout the brain's reward circuitry, in particular, in the mesolimbic dopamine system. In the past decade, investigations have begun to reveal potential genes involved in the risk for addiction through genomewide association studies. Additionally, a crucial role for epigenetic mechanisms, which mediate the enduring effects of drugs of abuse on the brain in animal models of addiction, has been established. This chapter focuses on recent evidence that genetic and epigenetic regulatory events underlie the changes throughout the reward circuitry in humans, as well as animal models of addiction. While further investigations are necessary, a picture of genetic and epigenetic mechanisms involved in addiction is beginning to emerge and the insight gained from these studies will be key to the identification of novel targets for improved diagnosis and treatment of addiction syndromes in humans.
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Affiliation(s)
- Deena M Walker
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Eric J Nestler
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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10
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Cannabis and Depression: A Twin Model Approach to Co-morbidity. Behav Genet 2017; 47:394-404. [PMID: 28466235 PMCID: PMC5486843 DOI: 10.1007/s10519-017-9848-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 04/13/2017] [Indexed: 01/25/2023]
Abstract
Cannabis use disorder (CUD) co-occurs with major depressive disorder (MDD) more frequently than would be expected by chance. However, studies to date have not produced a clear understanding of the mechanisms underlying this co-morbidity. Genetically informative studies can add valuable insight to this problem, as they allow the evaluation of competing models of co-morbidity. This study uses data from the Australian Twin Registry to compare 13 co-morbidity twin models initially proposed by Neale and Kendler (Am J Hum Genet 57:935–953, 1995). The analysis sample comprised 2410 male and female monozygotic and dizygotic twins (average age 32) who were assessed on CUD and MDD using the SSAGA-OZ interview. Data were analyzed in OpenMx. Of the 13 different co-morbidity models, two fit equally well: CUD causes MDD and Random Multiformity of CUD. Both fit substantially better than the Correlated Liabilities model. Although the current study cannot differentiate between them statistically, these models, in combination, suggest that CUD risk factors may causally influence the risk to develop MDD, but only when risk for CUD is high.
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11
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Nesvåg R, Reichborn-Kjennerud T, Gillespie NA, Knudsen GP, Bramness JG, Kendler KS, Ystrom E. Genetic and Environmental Contributions to the Association Between Cannabis Use and Psychotic-Like Experiences in Young Adult Twins. Schizophr Bull 2017; 43:644-653. [PMID: 27431873 PMCID: PMC5464089 DOI: 10.1093/schbul/sbw101] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
To investigate contributions of genetic and environmental risk factors and possible direction of causation for the relationship between symptoms of cannabis use disorders (CUD) and psychotic-like experiences (PLEs), a population-based sample of 2793 young adult twins (63.5% female, mean [range] age 28.2 [19-36] y) were assessed for symptoms of CUD and PLEs using the Composite International Diagnostic Interview. Latent risk of having symptoms of CUD or PLEs was modeled using Item Response Theory. Co-twin control analysis was performed to investigate effect of familiar confounding for the association between symptoms of CUD and PLEs. Biometric twin models were fitted to estimate the heritability, genetic and environmental correlations, and direction for the association. Lifetime use of cannabis was reported by 10.4 % of the twins, and prevalence of PLEs ranged from 0.1% to 2.2%. The incidence rate ratio of PLEs due to symptoms of CUD was 6.3 (95% CI, 3.9, 10.2) in the total sample and 3.5 (95% CI, 1.5, 8.2) within twin pairs. Heritability estimates for symptoms of CUD were 88% in men and women, and for PLEs 77% in men and 43% in women. The genetic and environmental correlations between symptoms of CUD and PLEs were 0.55 and 0.52, respectively. The model allowing symptoms of CUD to cause PLEs had a better fit than models specifying opposite or reciprocal directions of causation. The association between symptoms of CUD and PLEs is explained by shared genetic and environmental factors and direct effects from CUD to risk for PLEs.
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Affiliation(s)
- Ragnar Nesvåg
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway;,Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Ted Reichborn-Kjennerud
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway;,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Nathan A. Gillespie
- Virginia Institute for Psychiatric and Behavioral Genetics and Departments of Psychiatry, Virginia Commonwealth University, Richmond, VA
| | - Gun Peggy Knudsen
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
| | - Jørgen G. Bramness
- The Norwegian Centre for Addiction Research, University of Oslo, Oslo, Norway
| | - Kenneth S. Kendler
- Virginia Institute for Psychiatric and Behavioral Genetics and Departments of Psychiatry, Virginia Commonwealth University, Richmond, VA
| | - Eivind Ystrom
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway;,Department of Psychology, University of Oslo, Oslo, Norway;,School of Pharmacy, University of Oslo, Oslo, Norway
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Meyer AC, Bardo MT. Amphetamine self-administration and dopamine function: assessment of gene × environment interactions in Lewis and Fischer 344 rats. Psychopharmacology (Berl) 2015; 232:2275-85. [PMID: 25566972 PMCID: PMC4465863 DOI: 10.1007/s00213-014-3854-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 12/22/2014] [Indexed: 12/01/2022]
Abstract
RATIONALE Previous research suggests both genetic and environmental influences on substance abuse vulnerability. OBJECTIVES The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis. METHODS Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg). RESULTS "Addiction-prone" LEW rats had greater acquisition of amphetamine self-administration on a FR1 schedule compared to "addiction-resistant" F344 rats when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW rats. While no group differences were obtained in extracellular DA, gene × environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW rats showed attenuation in the amphetamine-induced decrease in DOPAC compared to F344 rats. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW rats. CONCLUSIONS The current results demonstrate gene × environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in nucleus accumbens (NAc) shell. However, the behavioral and neurochemical differences were not related directly, indicating that mechanisms independent of DA metabolism in NAc shell likely mediate the gene × environment effects in amphetamine self-administration.
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Affiliation(s)
- Andrew C. Meyer
- Department of Psychiatry, University of Vermont, Burlington, VT, USA
| | - Michael T. Bardo
- Department of Psychology, University of Kentucky, Lexington, KY, USA,Center for Drug Abuse Research Translation, Lexington, KY, USA
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13
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Ystrom E, Kendler KS, Reichborn-Kjennerud T. Early age of alcohol initiation is not the cause of alcohol use disorders in adulthood, but is a major indicator of genetic risk. A population-based twin study. Addiction 2014; 109:1824-32. [PMID: 24845951 PMCID: PMC4192000 DOI: 10.1111/add.12620] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 08/12/2013] [Accepted: 05/09/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND AIMS An early age of alcohol initiation (AAI) is associated with and has been hypothesized to be a cause of alcohol use disorders (AUD) in adulthood. Results from twin studies, however, indicate that AAI is an indicator of risk for AUD. We aimed to test a causal hypothesis versus a risk indicator hypothesis for the relationship between early AAI and AUD. DESIGN A population-based twin study using biometric twin modelling. SETTING Norway. PARTICIPANTS A population-based sample of 1336 Norwegian twins. MEASUREMENTS Life-time DSM-IV AUDs were assessed by structured clinical interview and AAI by questionnaire. FINDINGS The risk indicator model in which the association between AAI and AUD was explained by common vulnerability was the best fitted to the data. The heritability was 37% [95% confidence interval (CI) = 21%, 53%] for AAI and 62% (95% CI = 51%, 73%) for AUD. Genetic risk for AAI accounted for 44% (95% CI = 17%, 71%) of the total genetic risk for AUD and the correlation between genetic factors for AAI and AUD was -0.66 (95%CI -0.87, -0.46). Individual-specific environmental risk for AAI explained only 1% (95% CI = 0%, 3%) of the risk for AUD. Shared environmental factors did not influence AUD, but accounted for 25% (95% CI = 7%, 35%) of the variance in AAI. CONCLUSIONS The association between early age of alcohol initiation and alcohol use disorders in later life does not reflect a causal relationship, but is due almost entirely to common genetic risk factors.
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Affiliation(s)
- Eivind Ystrom
- Norwegian Institute of Public Health; Department of Genetics, Environment and Mental Health; Oslo; Norway
| | - Kenneth S. Kendler
- Virginia Institute for Psychiatric and Behavioral Genetics and Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Ted Reichborn-Kjennerud
- Norwegian Institute of Public Health; Department of Genetics, Environment and Mental Health; Oslo; Norway,Institute of Psychiatry, University of Oslo, Oslo, Norway
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14
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Abstract
Guided by rigorous methodology and a life-course perspective, the goal of this research is to address a gap in current knowledge on whether, when, and how strongly intergenerational continuity of substance use exists when examining age-equivalent and developmentally specific stages of the life course. Annual self-reported substance use measures were analyzed from a prospective, longitudinal, and nationally representative sample that originally consisted of 1,725 respondents and their families, who were then interviewed over a 27-year period from 1977 to 2004. Findings from multilevel random-intercept regression models provide support for intergenerational continuity when substance use occurs in emerging adulthood but not when limited to adolescence. Implications, limitations, and future research directions are discussed.
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Affiliation(s)
- Kelly E Knight
- Department of Criminal Justice and Criminology, Sam Houston State University , Hunstville, Texas , USA
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15
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Verweij KJH, Agrawal A, Nat NO, Creemers HE, Huizink AC, Martin NG, Lynskey MT. A genetic perspective on the proposed inclusion of cannabis withdrawal in DSM-5. Psychol Med 2013; 43:1713-1722. [PMID: 23194657 PMCID: PMC3733446 DOI: 10.1017/s0033291712002735] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Various studies support the inclusion of cannabis withdrawal in the diagnosis of cannabis use disorder (CUD) in the upcoming DSM-5. The aims of the current study were to (1) estimate the prevalence of DSM-5 cannabis withdrawal (criterion B), (2) estimate the role of genetic and environmental influences on individual differences in cannabis withdrawal and (3) determine the extent to which genetic and environmental influences on cannabis withdrawal overlap with those on DSM-IV-defined abuse/dependence. METHOD The sample included 2276 lifetime cannabis-using adult Australian twins. Cannabis withdrawal was defined in accordance with criterion B of the proposed DSM-5 revisions. Cannabis abuse/dependence was defined as endorsing one or more DSM-IV criteria of abuse or three or more dependence criteria. The classical twin model was used to estimate the genetic and environmental influences on variation in cannabis withdrawal, along with its covariation with abuse/dependence. RESULTS Of all the cannabis users, 11.9% met criteria for cannabis withdrawal. Around 50% of between-individual variation in withdrawal could be attributed to additive genetic variation, and the rest of the variation was mostly due to non-shared environmental influences. Importantly, the genetic influences on cannabis withdrawal almost completely (99%) overlapped with those on abuse/dependence. CONCLUSIONS We have shown that cannabis withdrawal symptoms exist among cannabis users, and that cannabis withdrawal is moderately heritable. Genetic influences on cannabis withdrawal are the same as those affecting abuse/dependence. These results add to the wealth of literature that recommends the addition of cannabis withdrawal to the diagnosis of DSM-5 CUD.
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Affiliation(s)
- K J H Verweij
- Department of Developmental Psychology, VU University, Amsterdam, The Netherlands
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Suchankova P, Jerlhag E, Jayaram-Lindström N, Nilsson S, Toren K, Rosengren A, Engel JA, Franck J. Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence. PLoS One 2013; 8:e61242. [PMID: 23579732 PMCID: PMC3620267 DOI: 10.1371/journal.pone.0061242] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 03/07/2013] [Indexed: 01/12/2023] Open
Abstract
The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.
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Affiliation(s)
- Petra Suchankova
- Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Elisabet Jerlhag
- Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- * E-mail:
| | - Nitya Jayaram-Lindström
- Department of Clinical Neuroscience, Division of Psychiatry at Karolinska Institutet, Stockholm, Sweden
| | - Staffan Nilsson
- Department of Mathematical Statistics, Institute of Mathematical Sciences at Chalmers University of Technology, Gothenburg, Sweden
| | - Kjell Toren
- Department of Occupational and Environmental Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Annika Rosengren
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Jörgen A. Engel
- Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Johan Franck
- Department of Clinical Neuroscience, Division of Psychiatry at Karolinska Institutet, Stockholm, Sweden
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Chachamovich E, Ding Y, Turecki G. Levels of aggressiveness are higher among alcohol-related suicides: results from a psychological autopsy study. Alcohol 2012; 46:529-36. [PMID: 22579734 DOI: 10.1016/j.alcohol.2012.03.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 03/13/2012] [Accepted: 03/29/2012] [Indexed: 01/09/2023]
Abstract
Suicide is one of the major causes of deaths worldwide. Several studies have showed that alcohol use disorders (AUD) are associated with suicide ideation, suicide attempts, and suicide completion. The majority of the theoretical conceptualization and the bulk of evidence on suicidal behavior and AUD are based on investigations of nonfatal cases because data on nonfatal suicidal behaviors are more readily available. This study aims to explore demographic, clinical, and behavioral dimensions in a large sample of alcohol-related suicides compared to an age-gender matched sample of non-AUD suicides to identify specific factors associated with AUD suicides. We conducted a psychological autopsy study with 158 pairs of AUD and non-AUD suicides. Findings showed that AUD suicides have lower educational level, more biological children and were more likely to be heavy smokers (OR=3.32). Cases were more likely to have family history of alcohol (OR=1.73) and drug abuse (OR=3.61). Subjects had similar prevalences of depressive disorders, anxiety disorders or psychotic disorders. AUD suicides were more likely to meet criteria for current cocaine abuse/dependence (OR=6.64). With respect to personality disorders, AUD suicides presented higher prevalence of Antisocial Personality Disorder (OR=4.68), and were less likely to meet criteria for Avoidant (OR=0.26) and Obsessive-Compulsive Personality Disorders (OR=0.35). Impulsivity scores were higher in AUD suicides (p=0.18), as well as aggression scores (p<0.001). Results form the conditional logistic regression models showed that cocaine abuse/dependence (OR=4.20) and Antisocial Personality Disorder (OR=6.24) were associated with AUD suicide. After controlling for impulsive-aggressive behaviors, levels of aggression were the only psychopathological feature statistically different between AUD and non-AUD suicides (OR=1.28). In conclusion, higher levels of aggressive behaviors are a specific characteristic of AUD suicides. Apart from substance-related diagnoses, AUD and non-AUD suicides have comparable Axis I psychiatric diagnoses and familial transmission of suicidal behavior.
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Affiliation(s)
- Eduardo Chachamovich
- McGill Group for Suicide Studies, Department of Psychiatry, McGill University, 6875 LaSalle Blvd, Montreal, Quebec, Canada H4H 1R3.
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18
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Log T, Skurtveit S, Selmer R, Tverdal A, Furu K, Hartz I. The association between prescribed opioid use for mothers and children: a record-linkage study. Eur J Clin Pharmacol 2012; 69:111-8. [DOI: 10.1007/s00228-012-1312-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 05/10/2012] [Indexed: 10/28/2022]
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Abstract
Epidemiological studies of substance use and substance use disorders (SUDs) have provided an abundance of data on the patterns of substance use in nationally representative samples across the world (Degenhardt et al. in PLoS Med 5(7):e141, 2008; Johnston et al. in Monitoring the future national survey results on drug use, 1975-2010, vol I, secondary school students. Institute for Social Research, Ann Arbor, MI, 2011; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). This paper presents a summary of the goals, methods, and recent findings on the epidemiology of substance use and disorders in the general population of adults and adolescents and describes the methods and findings on the genetic epidemiology of drug use disorders. The high 12-month prevalence rates of substance dependence in US adults (about 12 % for alcohol and 2-3 % for illicit drugs) approximate those of other mental disorders as well as chronic physical disorders with major public health impact. New findings from the nationally representative samples of US youth reveal that the lifetime prevalence of alcohol use disorders is approximately 8 % and illicit drug use disorders is 2-3 % (Merikangas et al. in J Am Acad Child Adolesc Psychiatry 49(10):980-989, 2010; Swendsen et al. in Arch Gen Psychiatry 69(4):390-398, 2012; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, Series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). The striking increase in prevalence rates from ages 13 to 18 highlight adolescence as the key period of development of SUDs. The application of genetic epidemiological studies has consistently demonstrated that genetic factors have a major influence on progression of substance use to dependence, whereas environmental factors unique to the individual play an important role in exposure and initial use of substances. Identification of specific susceptibility genes and environmental factors that influence exposure and progression of drug use may enhance our ability to prevent and treat SUDs.
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20
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Blanco C, Myers J, Kendler KS. Gambling, disordered gambling and their association with major depression and substance use: a web-based cohort and twin-sibling study. Psychol Med 2012; 42:497-508. [PMID: 21835089 PMCID: PMC4431979 DOI: 10.1017/s0033291711001401] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Relatively little is known about the environmental and genetic contributions to gambling frequency and disordered gambling (DG), the full continuum of gambling-related problems that includes pathological gambling (PG). METHOD A web-based sample (n=43,799 including both members of 609 twin and 303 sibling pairs) completed assessments of number of lifetime gambling episodes, DSM-IV criteria for PG, alcohol, nicotine and caffeine intake, and nicotine dependence (ND) and DSM-III-R criteria for lifetime major depression (MD). Twin modeling was performed using Mx. RESULTS In the entire cohort, symptoms of DG indexed a single dimension of liability. Symptoms of DG were weakly related to caffeine intake and moderately related to MD, consumption of cigarettes and alcohol, and ND. In twin and sibling pairs, familial resemblance for number of times gambled resulted from both familial-environmental (c²=42%) and genetic factors (a²=32%). For symptoms of DG, resemblance resulted solely from genetic factors (a²=83%). Bivariate analyses indicated a low genetic correlation between symptoms of DG and MD (r(a)=+0.14) whereas genetic correlations with DG symptoms were substantially higher with use of alcohol, caffeine and nicotine, and ND (ranging from +0.29 to +0.80). The results were invariant across genders. CONCLUSIONS Whereas gambling participation is determined by shared environmental and genetic factors, DG constitutes a single latent dimension that is largely genetically determined and more closely related to externalizing than internalizing behaviors. Because these findings are invariant across genders, they suggest that the etiological factors of DG are likely to be similar in men and women.
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Affiliation(s)
- C Blanco
- Department of Psychiatry, New York State Psychiatric Institute/Columbia University, NY, USA
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21
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Kerner B, Lambert CG, Muthén BO. Genome-wide association study in bipolar patients stratified by co-morbidity. PLoS One 2011; 6:e28477. [PMID: 22205951 PMCID: PMC3244396 DOI: 10.1371/journal.pone.0028477] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Accepted: 11/09/2011] [Indexed: 01/08/2023] Open
Abstract
Background Bipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors. Methodology In the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity. Results Bipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7×10−8). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9×10−8) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3×10−8) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations. Conclusion Conceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.
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Affiliation(s)
- Berit Kerner
- Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
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22
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Maher BS, Vladimirov VI, Latendresse SJ, Thiselton DL, McNamee R, Kang M, Bigdeli TB, Chen X, Riley BP, Hettema JM, Chilcoat H, Heidbreder C, Muglia P, Murrelle EL, Dick DM, Aliev F, Agrawal A, Edenberg HJ, Kramer J, Nurnberger J, Tischfield JA, Devlin B, Ferrell RE, Kirillova GP, Tarter RE, Kendler KS, Vanyukov MM. The AVPR1A gene and substance use disorders: association, replication, and functional evidence. Biol Psychiatry 2011; 70:519-27. [PMID: 21514569 PMCID: PMC4083653 DOI: 10.1016/j.biopsych.2011.02.023] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 02/01/2011] [Accepted: 02/03/2011] [Indexed: 12/23/2022]
Abstract
BACKGROUND The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms. METHODS In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD). RESULTS Associations (p ≤ .0008) were detected with three SNPs in the arginine vasopressin 1A receptor gene, AVPR1A, with a gene-wise p value of 3 × 10(-5). Bioinformatic evidence points to a role for rs11174811 (microRNA binding site disruption) in AVPR1A function. Based on literature implicating AVPR1A in social bonding, we tested spousal satisfaction as a mediator of the association of rs11174811 with the DUD. Spousal satisfaction was significantly associated with DUD in males (p < .0001). The functional AVPR1A SNP, rs11174811, was associated with spousal satisfaction in males (p = .007). Spousal satisfaction was a significant mediator of the relationship between rs11174811 and DUD. We also present replication of the association in males between rs11174811 and substance use in one clinically ascertained (n = 1399) and one epidemiologic sample (n = 2231). The direction of the association is consistent across the clinically-ascertained samples but reversed in the epidemiologic sample. Lastly, we found a significant impact of rs11174811 genotype on AVPR1A expression in a postmortem brain sample. CONCLUSIONS The findings of this study call for expansion of research into the role of the arginine vasopressin and other neuropeptide system variation in DUD liability.
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Affiliation(s)
- Brion S Maher
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
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23
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Olvera RL, Bearden CE, Velligan DI, Almasy L, Carless MA, Curran JE, Williamson DE, Duggirala R, Blangero J, Glahn DC. Common genetic influences on depression, alcohol, and substance use disorders in Mexican-American families. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:561-8. [PMID: 21557468 PMCID: PMC3112290 DOI: 10.1002/ajmg.b.31196] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 03/25/2011] [Indexed: 01/01/2023]
Abstract
Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community-ascertained sample of Mexican-American families. A total of 1,122 Mexican-American individuals from 71 extended pedigrees participated in the study. All subjects received in-person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty-five percent of the sample met criteria for DSM-IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h(2) = 0.393 (P = 3.7 × 10(-6)). Heritability estimates were higher for recurrent depression (h(2) = 0.463, P = 4.0 × 10(-6)) and early onset depression (h(2) = 0.485, P = 8.5 × 10(-5)). While the genetic correlation between major depression and alcohol use disorders was significant (ρ(g) = 0.58, P = 7 × 10(-3)), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US-born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican-American population is similar to that reported in other populations.
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Affiliation(s)
- R L Olvera
- Department of Psychiatry, University of Texas Health Science Center San Antonio, USA.
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Røysamb E, Kendler KS, Tambs K, Orstavik RE, Neale MC, Aggen SH, Torgersen S, Reichborn-Kjennerud T. The joint structure of DSM-IV Axis I and Axis II disorders. JOURNAL OF ABNORMAL PSYCHOLOGY 2011; 120:198-209. [PMID: 21319931 DOI: 10.1037/a0021660] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The Diagnostic and Statistical Manual (4th ed. [DSM-IV]; American Psychiatric Association, 1994) distinction between clinical disorders on Axis I and personality disorders on Axis II has become increasingly controversial. Although substantial comorbidity between axes has been demonstrated, the structure of the liability factors underlying these two groups of disorders is poorly understood. The aim of this study was to determine the latent factor structure of a broad set of common Axis I disorders and all Axis II personality disorders and thereby to identify clusters of disorders and account for comorbidity within and between axes. Data were collected in Norway, through a population-based interview study (N = 2,794 young adult twins). Axis I and Axis II disorders were assessed with the Composite International Diagnostic Interview (CIDI) and the Structured Interview for DSM-IV Personality (SIDP-IV), respectively. Exploratory and confirmatory factor analyses were used to investigate the underlying structure of 25 disorders. A four-factor model fit the data well, suggesting a distinction between clinical and personality disorders as well as a distinction between broad groups of internalizing and externalizing disorders. The location of some disorders was not consistent with the DSM-IV classification; antisocial personality disorder belonged primarily to the Axis I externalizing spectrum, dysthymia appeared as a personality disorder, and borderline personality disorder appeared in an interspectral position. The findings have implications for a meta-structure for the DSM.
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Affiliation(s)
- Espen Røysamb
- Norwegian Institute of Public Health and University of Oslo, Norway.
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Kendler KS, Aggen SH, Knudsen GP, Røysamb E, Neale MC, Reichborn-Kjennerud T. The structure of genetic and environmental risk factors for syndromal and subsyndromal common DSM-IV axis I and all axis II disorders. Am J Psychiatry 2011; 168:29-39. [PMID: 20952461 PMCID: PMC3126864 DOI: 10.1176/appi.ajp.2010.10030340] [Citation(s) in RCA: 246] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The authors sought to clarify the structure of the genetic and environmental risk factors for 22 DSM-IV disorders: 12 common axis I disorders and all 10 axis II disorders. METHOD The authors examined syndromal and subsyndromal axis I diagnoses and five categories reflecting number of endorsed criteria for axis II disorders in 2,111 personally interviewed young adult members of the Norwegian Institute of Public Health Twin Panel. RESULTS Four correlated genetic factors were identified: axis I internalizing, axis II internalizing, axis I externalizing, and axis II externalizing. Factors 1 and 2 and factors 3 and 4 were moderately correlated, supporting the importance of the internalizing-externalizing distinction. Five disorders had substantial loadings on two factors: borderline personality disorder (factors 3 and 4), somatoform disorder (factors 1 and 2), paranoid and dependent personality disorders (factors 2 and 4), and eating disorders (factors 1 and 4). Three correlated environmental factors were identified: axis II disorders, axis I internalizing disorders, and externalizing disorders versus anxiety disorders. CONCLUSIONS Common axis I and II psychiatric disorders have a coherent underlying genetic structure that reflects two major dimensions: internalizing versus externalizing, and axis I versus axis II. The underlying structure of environmental influences is quite different. The organization of common psychiatric disorders into coherent groups results largely from genetic, not environmental, factors. These results should be interpreted in the context of unavoidable limitations of current statistical methods applied to this number of diagnostic categories.
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Abstract
BACKGROUND Psychiatric conditions in which symptoms arise involuntarily ('diseases') might be assumed to be more heritable than those in which choices are essential (behavioral disorders). We sought to determine whether psychiatric 'diseases' (Alzheimer's disease, schizophrenia, and mood and anxiety disorders) are more heritable than behavioral disorders (substance use disorders and anorexia nervosa). METHOD We reviewed the literature for recent quantitative summaries of heritabilities. When these were unavailable, we calculated weighted mean heritabilities from twin studies meeting modern methological standards. RESULTS Heritability summary estimates were as follows: bipolar disorder (85%), schizophrenia (81%), Alzheimer's disease (75%), cocaine use disorder (72%), anorexia nervosa (60%), alcohol dependence (56%), sedative use disorder (51%), cannabis use disorder (48%), panic disorder (43%), stimulant use disorder (40%), major depressive disorder (37%), and generalized anxiety disorder (28%). CONCLUSIONS No systematic relationship exists between the disease-like character of a psychiatric disorder and its heritability; many behavioral disorders seem to be more heritable than conditions commonly construed as diseases. These results suggest an error in 'common-sense' assumptions about the etiology of psychiatric disorders. That is, among psychiatric disorders, there is no close relationship between the strength of genetic influences and the etiologic importance of volitional processes.
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Affiliation(s)
- O J Bienvenu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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Verweij KJ, Zietsch BP, Lynskey MT, Medland SE, Neale MC, Martin NG, Boomsma DI, Vink JM. Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction 2010; 105:417-30. [PMID: 20402985 PMCID: PMC2858354 DOI: 10.1111/j.1360-0443.2009.02831.x] [Citation(s) in RCA: 189] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Because cannabis use is associated with social, physical and psychological problems, it is important to know what causes some individuals to initiate cannabis use and a subset of those to become problematic users. Previous twin studies found evidence for both genetic and environmental influences on vulnerability, but due to considerable variation in the results it is difficult to draw clear conclusions regarding the relative magnitude of these influences. METHODS A systematic literature search identified 28 twin studies on cannabis use initiation and 24 studies on problematic cannabis use. The proportion of total variance accounted for by genes (A), shared environment (C) and unshared environment (E) in (i) initiation of cannabis use and (ii) problematic cannabis use was calculated by averaging corresponding A, C and E estimates across studies from independent cohorts and weighting by sample size. RESULTS For cannabis use initiation, A, C and E estimates were 48%, 25% and 27% in males and 40%, 39% and 21% in females. For problematic cannabis use A, C and E estimates were 51%, 20% and 29% for males and 59%, 15% and 26% for females. Confidence intervals of these estimates are considerably narrower than those in the source studies. CONCLUSIONS Our results indicate that vulnerability to both cannabis use initiation and problematic use was influenced significantly by A, C and E. There was a trend for a greater C and lesser A component for cannabis use initiation compared to problematic use for females.
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Affiliation(s)
- Karin J.H. Verweij
- Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, School of Psychology, University of Queensland, Brisbane, Queensland, Australia, Department of Biological Psychology, VU University, Amsterdam, the Netherlands
| | - Brendan P. Zietsch
- Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, School of Psychology, University of Queensland, Brisbane, Queensland, Australia
| | - Michael T. Lynskey
- Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
| | - Sarah E. Medland
- Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
| | - Michael C. Neale
- Virginia Institute for Psychiatric and Behavioural Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Nicholas G. Martin
- Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
| | - Dorret I. Boomsma
- Department of Biological Psychology, VU University, Amsterdam, the Netherlands
| | - Jacqueline M. Vink
- Department of Biological Psychology, VU University, Amsterdam, the Netherlands
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28
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Abstract
BACKGROUND The extant major psychiatric classifications DSM-IV and ICD-10 are purportedly atheoretical and largely descriptive. Although this achieves good reliability, the validity of a medical diagnosis is greatly enhanced by an understanding of the etiology. In an attempt to group mental disorders on the basis of etiology, five clusters have been proposed. We consider the validity of the fifth cluster, externalizing disorders, within this proposal. METHOD We reviewed the literature in relation to 11 validating criteria proposed by the Study Group of the DSM-V Task Force, in terms of the extent to which these criteria support the idea of a coherent externalizing spectrum of disorders. RESULTS This cluster distinguishes itself by the central role of disinhibitory personality in mental disorders spread throughout sections of the current classifications, including substance dependence, antisocial personality disorder and conduct disorder. Shared biomarkers, co-morbidity and course offer additional evidence for a valid cluster of externalizing disorders. CONCLUSION Externalizing disorders meet many of the salient criteria proposed by the Study Group of the DSM-V Task Force to suggest a classification cluster.
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Affiliation(s)
- R F Krueger
- Department of Psychology, Washington University in St Louis, St Louis, MO 63130-4899, USA.
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29
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Tambs K, Czajkowsky N, Røysamb E, Neale MC, Reichborn-Kjennerud T, Aggen SH, Harris JR, Ørstavik RE, Kendler KS. Structure of genetic and environmental risk factors for dimensional representations of DSM-IV anxiety disorders. Br J Psychiatry 2009; 195:301-7. [PMID: 19794197 PMCID: PMC3010208 DOI: 10.1192/bjp.bp.108.059485] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Twin data permit decomposition of comorbidity into genetically and environmentally derived correlations. No previous twin study includes all major forms of anxiety disorder. AIMS To estimate the degree to which genetic and environmental risk factors are shared rather than unique to dimensionally scored panic disorder, generalised anxiety disorder, phobias, obsessive-compulsive disorder and post-traumatic stress disorder. METHOD Data obtained from 2801 young-adult Norwegian twins by means of the Composite International Diagnostic Interview were analysed with the Mx program. RESULTS A multivariate common factor model fitted best. The latent liability to all anxiety disorders was substantially more heritable (54%) than the individual disorders (23% to 40%). Most of the genetic effect was common to the disorders. Genes contributed just over 50% to the covariance between liabilities. CONCLUSIONS The five anxiety disorders all share genetic and environmental risk factors. This has implications for the revision of the anxiety disorder section in DSM-V.
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Affiliation(s)
- Kristian Tambs
- Department of Mental Health, Norwegian Institute of Public Health, Box 4404 Nydalen, 0403 Oslo 3, Norway.
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Uhl GR, Drgon T, Li CY, Johnson C, Liu QR. Smoking and smoking cessation in disadvantaged women: assessing genetic contributions. Drug Alcohol Depend 2009; 104 Suppl 1:S58-63. [PMID: 19442458 PMCID: PMC9295906 DOI: 10.1016/j.drugalcdep.2009.03.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2008] [Revised: 02/26/2009] [Accepted: 03/24/2009] [Indexed: 12/01/2022]
Abstract
Abundant evidence from family, adoption and twin studies points to large genetic contributions to individual differences in vulnerability to develop dependence on one or more addictive substances, including tobacco. Twin data suggests that much of this genetic vulnerability is shared by individuals who are dependent on a variety of addictive substances. Interestingly, some twin data also supports substantial differences in the apparent heritability of nicotine dependence in women as environmental conditions become more permissive for their smoking. In addition, twin studies also support the idea that ability to quit smoking displays substantial heritability, and that this heritable influence overlaps partially with genetic influences on nicotine dependence. Candidate gene molecular genetic studies and genome wide association studies of substance dependence and ability to quit smoking each document apparent polygenic influences that identify lists of genes that display partial overlap, as expected from classical genetic studies. More of these genes are expressed in the brain than would be anticipated by chance. These lists of genes overlap significantly with those identified in molecular genetic studies of individual differences in cognitive abilities, frontal lobe brain volumes as well as personality and psychiatric phenotypes. Though most available genome wide association data do not separate results by gender, it may be notable that few of these genes lie on sex chromosomes. These data provide a substrate to improve understanding of nicotine dependence, the ability to quit smoking, the potential for less permissive environments to restrict the expression of genetic influences on smoking and the possibility that brain features that underlie phenotypes such as individual differences in cognitive abilities might interact with environmental features that are especially prominent for disadvantaged women to provide special circumstances that should be considered in prevention and treatment efforts to reduce smoking.
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Affiliation(s)
- George R Uhl
- Molecular Neurobiology Branch, NIH-IRP (NIDA), Baltimore, MD 21224, USA.
| | - Tomas Drgon
- Molecular Neurobiology Branch, NIH-IRP (NIDA) Baltimore, Maryland, USA
| | - Chuan-Yun Li
- Molecular Neurobiology Branch, NIH-IRP (NIDA) Baltimore, Maryland, USA,National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University. Beijing, China
| | - Catherine Johnson
- Molecular Neurobiology Branch, NIH-IRP (NIDA) Baltimore, Maryland, USA
| | - Qing-Rong Liu
- Molecular Neurobiology Branch, NIH-IRP (NIDA) Baltimore, Maryland, USA
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31
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Abstract
AIM Twin studies have shown that cannabis use disorders (abuse/dependence) are highly heritable. This review aims to: (i) review existing linkage studies of cannabis use disorders and (ii) review gene association studies, to identify potential candidate genes, including those that have been tested for composite substance use disorders and (iii) to highlight challenges in the genomic study of cannabis use disorders. METHODS Peer-reviewed linkage and candidate gene association studies are reviewed. RESULTS Four linkage studies are reviewed: results from these have homed in on regions on chromosomes 1, 3, 4, 9, 14, 17 and 18, which harbor candidates of predicted biological relevance, such as monoglyceride lipase (MGLL) on chromosome 3, but also novel genes, including ELTD1[epidermal growth factor (EGF), latrophilin and seven transmembrane domain containing 1] on chromosome 1. Gene association studies are presented for (a) genes posited to have specific influences on cannabis use disorders: CNR1, CB2, FAAH, MGLL, TRPV1 and GPR55 and (b) genes from various neurotransmitter systems that are likely to exert a non-specific influence on risk of cannabis use disorders, e.g. GABRA2, DRD2 and OPRM1. CONCLUSIONS There are challenges associated with (i) understanding biological complexity underlying cannabis use disorders (including the need to study gene-gene and gene-environment interactions), (ii) using diagnostic versus quantitative phenotypes, (iii) delineating which stage of cannabis involvement (e.g. use versus misuse) genes influence and (iv) problems of sample ascertainment.
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Affiliation(s)
- Arpana Agrawal
- Washington University School of Medicine, Department of Psychiatry, St Louis, MO 63110, USA.
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Mazzeo SE, Mitchell KS, Bulik CM, Reichborn-Kjennerud T, Kendler KS, Neale MC. Assessing the heritability of anorexia nervosa symptoms using a marginal maximal likelihood approach. Psychol Med 2009; 39:463-473. [PMID: 18485259 PMCID: PMC2640444 DOI: 10.1017/s0033291708003310] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Assessment of eating disorders at the symptom level can facilitate the refinement of phenotypes. We examined genetic and environmental contributions to liability to anorexia nervosa (AN) symptoms in a population-based twin sample using a genetic common pathway model. METHOD Participants were from the Norwegian Institute of Public Health Twin Panel (NIPHTP) and included all female monozygotic (MZ; 448 complete pairs and four singletons) and dizygotic (DZ; 263 complete pairs and four singletons) twins who completed the Composite International Diagnostic Interview (CIDI) assessing DSM-IV Axis I and ICD-10 criteria. Responses to items assessing AN symptoms were included in a model fitted using the marginal maximum likelihood (MML) approach. RESULTS Heritability of the overall AN diagnosis was moderate [a2=0.22, 95% confidence interval (CI) 0.0-0.50] whereas heritabilities of the specific items varied. Heritability estimates for weight loss items were moderate (a2=0.31-0.34) and items assessing weight concern when at a low weight were smaller (0.18-0.29). Additive genetic factors contributed little to the variance of amenorrhea, which was most strongly influenced by unshared environment (a2=0.16, e2=0.71). CONCLUSIONS AN symptoms are differentially heritable. Specific criteria such as those related to body weight and weight loss history represent more biologically driven potential endophenotypes or liability indices. The results regarding weight concern differ somewhat from those of previous studies, highlighting the importance of assessing genetic and environmental influences on variance of traits within specific subgroups of interest.
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Affiliation(s)
- S E Mazzeo
- Department of Psychology, Virginia Commonwealth University, Richmond, VA 23284-2018, USA.
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Uhl GR, Drgon T, Johnson C, Liu QR. Addiction genetics and pleiotropic effects of common haplotypes that make polygenic contributions to vulnerability to substance dependence. J Neurogenet 2009; 23:272-82. [PMID: 19152208 DOI: 10.1080/01677060802572929] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Abundant evidence from family, adoption, and twin studies point to large genetic contributions to individual differences in vulnerability to develop dependence on one or more addictive substances. Twin data suggest that most of this genetic vulnerability is shared by individuals who are dependent on a variety of addictive substances. Molecular genetic studies, especially genomewide and candidate gene association studies, have elucidated common haplotypes in dozens of genes that appear to make polygenic contributions to vulnerability to developing dependence. Most genes that harbor currently identified addiction-associated haplotypes are expressed in the brain. Haplotypes in many of the same genes are identified in genomewide association studies that compare allele frequencies in substance dependent vs. control individuals from European, African, and Asian racial/ethnic backgrounds. Many of these addiction-associated haplotypes display pleiotropic influences on a variety of related brain-based phenotypes that display 1) substantial heritability and 2) clinical cooccurence with substance dependence.
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Affiliation(s)
- George R Uhl
- Molecular Neurobiology Branch, NIH-IRP (NIDA), Baltimore, Maryland 21224, USA.
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34
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Uhl GR, Drgon T, Johnson C, Li CY, Contoreggi C, Hess J, Naiman D, Liu QR. Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects. Ann N Y Acad Sci 2008; 1141:318-81. [PMID: 18991966 PMCID: PMC3922196 DOI: 10.1196/annals.1441.018] [Citation(s) in RCA: 131] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Genome-wide association (GWA) can elucidate molecular genetic bases for human individual differences in complex phenotypes that include vulnerability to addiction. Here, we review (a) evidence that supports polygenic models with (at least) modest heterogeneity for the genetic architectures of addiction and several related phenotypes; (b) technical and ethical aspects of importance for understanding GWA data, including genotyping in individual samples versus DNA pools, analytic approaches, power estimation, and ethical issues in genotyping individuals with illegal behaviors; (c) the samples and the data that shape our current understanding of the molecular genetics of individual differences in vulnerability to substance dependence and related phenotypes; (d) overlaps between GWA data sets for dependence on different substances; and (e) overlaps between GWA data for addictions versus other heritable, brain-based phenotypes that include bipolar disorder, cognitive ability, frontal lobe brain volume, the ability to successfully quit smoking, neuroticism, and Alzheimer's disease. These convergent results identify potential targets for drugs that might modify addictions and play roles in these other phenotypes. They add to evidence that individual differences in the quality and quantity of brain connections make pleiotropic contributions to individual differences in vulnerability to addictions and to related brain disorders and phenotypes. A "connectivity constellation" of brain phenotypes and disorders appears to receive substantial pathogenic contributions from individual differences in a constellation of genes whose variants provide individual differences in the specification of brain connectivities during development and in adulthood. Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes.
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Affiliation(s)
- George R Uhl
- Molecular Neurobiology Branch, National Institutes of Health (NIH), Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA), Baltimore, MD 21224, USA.
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35
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Agrawal A, Lynskey MT. Are there genetic influences on addiction: evidence from family, adoption and twin studies. Addiction 2008; 103:1069-81. [PMID: 18494843 DOI: 10.1111/j.1360-0443.2008.02213.x] [Citation(s) in RCA: 256] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
AIMS In this exciting era of gene discovery, we review evidence from family, adoption and twin studies that examine the genetic basis for addiction. With a focus on the classical twin design that utilizes data on monozygotic and dizygotic twins, we discuss support in favor of heritable influences on alcohol, nicotine, cannabis and other illicit drug dependence. METHODS We review whether these genetic factors also influence earlier stages (e.g. experimentation) of the addictive process and whether there are genetic influences specific to each psychoactive substance. RESULTS Converging evidence from these studies supports the role of moderate to high genetic influences on addiction with estimates ranging from 0.30 to 0.70. The changing role of these heritable factors as a function of gender, age and cultural characteristics is also discussed. We highlight the importance of the interplay between genes and the environment as it relates to risk for addiction and the utility of the children-of-twins design for emerging studies of gene-environment interaction is presented. CONCLUSIONS Despite the advances being made by low-cost high-throughput whole genome association assays, we posit that information garnered from twin studies, especially extended twin designs with power to examine gene-environment interactions, will continue to form the foundation for genomic research.
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Affiliation(s)
- Arpana Agrawal
- Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
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36
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Iacono WG, Malone SM, McGue M. Behavioral Disinhibition and the Development of Early-Onset Addiction: Common and Specific Influences. Annu Rev Clin Psychol 2008; 4:325-48. [PMID: 18370620 DOI: 10.1146/annurev.clinpsy.4.022007.141157] [Citation(s) in RCA: 380] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- William G. Iacono
- Department of Psychology, University of Minnesota, Minneapolis, Minnesota 55455; ,
| | - Stephen M. Malone
- Department of Psychology, University of Minnesota, Minneapolis, Minnesota 55455; ,
| | - Matt McGue
- Department of Psychology, University of Minnesota, Minneapolis, Minnesota 55455; ,
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Pears K, Capaldi DM, Owen LD. Substance use risk across three generations: the roles of parent discipline practices and inhibitory control. PSYCHOLOGY OF ADDICTIVE BEHAVIORS 2007; 21:373-86. [PMID: 17874888 PMCID: PMC1988842 DOI: 10.1037/0893-164x.21.3.373] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
This study used 3 generations and 21 years of prospective data to test models of intergenerational transmission of substance use and substance use risk. Thus, the study extends prior studies in the field that have focused predominantly on substance abuse. The association between the grandparental generation's (G1 mother and father) and the parental generation's (G2 father) alcohol use and illicit drug use was hypothesized to be mediated by G2's poor inhibitory control. Additionally, G1's poor discipline of G2 was hypothesized to be directly associated with G2's substance use as well as to partially mediate the association between G1's substance use and G2's inhibitory control. In turn, G2's substance use in late adolescence was expected to be associated with its offspring's (G3) poor inhibitory control at age 3 years. Findings partially supported the predictions and varied by substance. For alcohol use, only cross-generational associations in use were found. For illicit drugs, both poor inhibitory control and poor discipline played some mediational role in cross-generational use.
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Uhl GR, Drgon T, Johnson C, Fatusin OO, Liu QR, Contoreggi C, Li CY, Buck K, Crabbe J. "Higher order" addiction molecular genetics: convergent data from genome-wide association in humans and mice. Biochem Pharmacol 2007; 75:98-111. [PMID: 17764662 PMCID: PMC3282179 DOI: 10.1016/j.bcp.2007.06.042] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2007] [Revised: 06/26/2007] [Accepted: 06/28/2007] [Indexed: 02/05/2023]
Abstract
Family, adoption and twin data each support substantial heritability for addictions. Most of this heritable influence is not substance-specific. The overlapping genetic vulnerability for developing dependence on a variety of addictive substances suggests large roles for "higher order" pharamacogenomics in addiction molecular genetics. We and others have now completed genome-wide association (GWA) studies of DNAs from individuals with dependence on a variety of addictive substances versus appropriate controls. Recently reported replicated GWA observations identify a number of genes based on comparisons between controls and European-American and African-American polysubstance abusers. Here we review the convergence between these results and data that compares control samples and (a) alcohol-dependent European-Americans, (b) methamphetamine-dependent Asians and (c) nicotine dependent samples from European backgrounds. We also compare these human data to quantitative trait locus (QTL) results from studies of addiction-related phenotypes in mice that focus on alcohol, methamphetamine and barbiturates. These comparisons support a genetic architecture built from largely polygenic contributions of common allelic variants to dependence on a variety of legal and illegal substances. Many of the gene variants identified in this way are likely to alter specification and maintenance of neuronal connections.
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Affiliation(s)
- George R Uhl
- Molecular Neurobiology Branch, NIH-IRP (NIDA), Suite 3510, 333 Cassell Drive Baltimore, MD 21224, USA.
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