Jorim J Tielbeek1,2,3, Ada Johansson4,5,6, Tinca J C Polderman1, Marja-Riitta Rautiainen7,8,9, Philip Jansen1,10, Michelle Taylor11, Xiaoran Tong12, Qing Lu12, Alexandra S Burt13, Henning Tiemeier10,14,15, Essi Viding16, Robert Plomin16, Nicholas G Martin3, Andrew C Heath17, Pamela A F Madden17, Grant Montgomery3, Kevin M Beaver18,19, Irwin Waldman20, Joel Gelernter21,22, Henry R Kranzler23,24, Lindsay A Farrer25, John R B Perry26, Marcus Munafò11, Devon LoParo20, Tiina Paunio7,8,9, Jari Tiihonen27,28, Sabine E Mous14, Irene Pappa14, Christiaan de Leeuw1, Kyoko Watanabe1, Anke R Hammerschlag1,10, Jessica E Salvatore29, Fazil Aliev30,31, Tim B Bigdeli32, Danielle Dick33, Stephen V Faraone34,35, Arne Popma2, Sarah E Medland3, Danielle Posthuma1,36. 1. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 2. Department of Child and Adolescent Psychiatry, VU University Medical Center, Amsterdam, the Netherlands. 3. QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. 4. Department of Psychology and Speech-Language Pathology, University of Turku, Turku, Finland. 5. Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 6. Department of Psychology, Faculty of Arts, Psychology, and Theology, Åbo Akademi University, Turku, Finland. 7. National Institute for Health and Welfare, Helsinki, Finland. 8. Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio. 9. Department of Psychiatry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 10. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. 11. Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, England. 12. Department of Epidemiology and Biostatistics, Michigan State University, East Lansing. 13. Department of Psychology, Michigan State University, East Lansing. 14. Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, the Netherlands. 15. Department of Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands. 16. Division of Psychology and Language Sciences, University College London, London, England. 17. Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri. 18. College of Criminology and Criminal Justice, Florida State University, Tallahassee. 19. Center for Social and Humanities Research, King Abdulaziz University, Jeddah, Saudi Arabia. 20. Psychology Department, Emory University, Atlanta, Georgia. 21. Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 22. Veterans Affairs (VA) Connecticut Healthcare Center, New Haven. 23. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia. 24. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania. 25. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts. 26. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, England. 27. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 28. Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland. 29. Department of Psychology and the Virginia Institute for Psychiatric and Behavioural Genetics, Virginia Commonwealth University, Richmond. 30. Department of African American Studies, Virginia Commonwealth University, Richmond. 31. Faculty of Business, Karabuk University, Karabuk, Turkey. 32. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond. 33. Department of Psychology, African American Studies, and Human & Molecular Genetics, Virginia Commonwealth University, Richmond. 34. Department of Psychiatry and Behavioral Sciences, Psychiatric Genetic Epidemiology and Neurobiology Laboratory, SUNY Upstate Medical University, Syracuse, New York. 35. Department of Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory, SUNY Upstate Medical University, Syracuse, New York. 36. Department of Clinical Genetics, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
Abstract
Importance: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected. Conclusions and Relevance: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
Importance: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatrictraits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected. Conclusions and Relevance: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
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