Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

Jorim J Tielbeek¹, Emil Uffelmann², Benjamin S Williams³, Lucía Colodro-Conde⁴, Éloi Gagnon⁵, Travis T Mallard⁶, Brandt E Levitt⁷, Philip R Jansen², Ada Johansson⁸, Hannah M Sallis⁹, Giorgio Pistis¹⁰, Gretchen R B Saunders¹¹, Andrea G Allegrini¹², Kaili Rimfeld¹², Bettina Konte¹³, Marieke Klein¹⁴, Annette M Hartmann¹³, Jessica E Salvatore¹⁵, Ilja M Nolte¹⁶, Ditte Demontis¹⁷, Anni L K Malmberg¹⁸, S Alexandra Burt¹⁹, Jeanne E Savage², Karen Sugden³, Richie Poulton²⁰, Kathleen Mullan Harris²¹, Scott Vrieze¹¹, Matt McGue¹¹, William G Iacono¹¹, Nina Roth Mota¹⁴, Jonathan Mill²², Joana F Viana²³, Brittany L Mitchell²⁴, Jose J Morosoli⁴, Till F M Andlauer²⁵, Isabelle Ouellet-Morin²⁶, Richard E Tremblay²⁷, Sylvana M Côté²⁸, Jean-Philippe Gouin²⁹, Mara R Brendgen³⁰, Ginette Dionne⁵, Frank Vitaro³¹, Michelle K Lupton²⁴, Nicholas G Martin²⁴; COGA Consortium; Spit for Science Working Group; Enrique Castelao¹⁰, Katri Räikkönen¹⁸, Johan G Eriksson³², Jari Lahti¹⁸, Catharina A Hartman³³, Albertine J Oldehinkel³³, Harold Snieder¹⁶, Hexuan Liu³⁴, Martin Preisig¹⁰, Alyce Whipp³⁵, Eero Vuoksimaa³⁵, Yi Lu³⁶, Patrick Jern⁸, Dan Rujescu¹³, Ina Giegling¹³, Teemu Palviainen³⁵, Jaakko Kaprio³⁵, Kathryn Paige Harden³⁷, Marcus R Munafò⁹, Geneviève Morneau-Vaillancourt⁵, Robert Plomin¹², Essi Viding³⁸, Brian B Boutwell³⁹, Fazil Aliev⁴⁰, Danielle M Dick⁴⁰, Arne Popma⁴¹, Stephen V Faraone⁴², Anders D Børglum¹⁷, Sarah E Medland⁴, Barbara Franke⁴³, Michel Boivin⁵, Jean-Baptiste Pingault⁴⁴, Jeffrey C Glennon⁴⁵, J C Barnes³⁴, Simon E Fisher⁴⁶, Terrie E Moffitt³, Avshalom Caspi³, Tinca J C Polderman⁴¹, Danielle Posthuma²

Collaborators, Affiliations

Affiliations

¹ Center for Neurogenomics and Cognitive Research, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands. j.j.tielbeek@vu.nl.
² Center for Neurogenomics and Cognitive Research, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands.
³ Department of Psychology and Neuroscience, Trinity College of Arts and Sciences, Duke University, 2020 West Main Street, Durham, NC, 27705, USA.
⁴ Psychiatric Genetics, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
⁵ Research Unit on Children's Psychosocial Maladjustment, École de psychologie, Université Laval, 2523 Allée des Bibliothèques, Quebec City, QC, G1V 0A6, Canada.
⁶ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Carolina Population Center, University of North Carolina at Chapel Hill, 123 Franklin St, Chapel Hill, NC, 27516, USA.
⁸ Department of Psychology, Faculty of Arts, Psychology, and Theology, Åbo Akademi University, Tuomiokirkontori 3, FI-20500, Turku, Finland.
⁹ MRC Integrative Epidemiology Unit, University of Bristol, Oakfield Road, Bristol, BS8 2BN, UK.
¹⁰ Center for Psychiatric Epidemiology and Psychopathology, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Route de Cery 25, CH-1008, Prilly, Vaud, Switzerland.
¹¹ Department of Psychology, University of Minnesota, 75 E. River Road, Minneapolis, MN, 55455, USA.
¹² Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, DeCrespigny Park, Denmark Hill, London, SE5 8AF, UK.
¹³ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
¹⁴ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Groteplein 10, 6500 HB, Nijmegen, The Netherlands.
¹⁵ Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.
¹⁶ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
¹⁷ iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000, Aarhus C, Aarhus, Denmark.
¹⁸ Department of Psychology and Logopedics, University of Helsinki, Haartmaninkatu 3, 00014, Helsinki, Finland.
¹⁹ Michigan State University, East Lansing, MI, USA.
²⁰ Dunedin Multidisciplinary Health and Development Research Unit, Department of Psychology, Dunedin, New Zealand.
²¹ Department of Sociology, University of North Carolina at Chapel Hill, CB# 3210, 201 Hamilton Hall, Chapel Hill, NC, 27599, USA.
²² University of Exeter Medical School, University of Exeter, Exeter, UK.
²³ The Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, Birmingham, UK.
²⁴ Genetic Epidemiology, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
²⁵ Department of Neurology, Technical University of Munich, 22 Ismaninger St., 81675, Munich, Germany.
²⁶ Research Unit on Children's Psychosocial Maladjustment, École de criminologie, Université of Montreal, 3150 Rue Jean-Brillant, Montreal, QC, H3T 1N8, Canada.
²⁷ Research Unit on Children's Psychosocial Maladjustment, Département de pédiatrie et de psychologie, University of Montreal, 90 Avenue Vincent d'Indy, Montreal, QC, H2V 2S9, Canada.
²⁸ Research Unit on Children's Psychosocial Maladjustment, CHU Ste-Justine Research Center and Department of Social and Preventive Medicine, University of Montreal, 3175 Chemin de la Côte Ste-Catherine, Montreal, QC, H3T 1C5, Canada.
²⁹ Department of Psychology, Concordia University, 7141 Sherbrooke St. West, Montreal, QC, H4B 1R6, Canada.
³⁰ Research Unit on Children's Psychosocial Maladjustment, Département de psychologie, Université du Québec à Montréal, CP 8888 succursale Centre-ville, Montreal, QC, H3C 3P8, Canada.
³¹ Research Unit on Children's Psychosocial Maladjustment, CHU Sainte-Justine Research Center and University of Montreal, 3175 Chemin de la Côte Ste-Catherine, Montreal, QC, H3T 1C5, Canada.
³² Department of General Practice and Primary Health Care, University of Helsinki, Tukholmankatu 8 B, Helsinki, Finland.
³³ Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
³⁴ School of Criminal Justice, University of Cincinnati, 2840 Bearcat Way, Cincinnati, OH, 45221, USA.
³⁵ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, PO Box 4, (Yliopistonkatu 3), 00014, Helsinki, Finland.
³⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden.
³⁷ Department of Psychology and Population Research Center, University of Texas at Austin, 108 E Dean Keeton Stop #A8000, Austin, TX, 78712, USA.
³⁸ Division of Psychology and Language Sciences, University College London, London, UK.
³⁹ School of Applied Sciences, University of Mississippi, John D. Bower School of Population Health, University of Mississippi Medical Center, 84 Dormitory Row West, University, MS, 38677, USA.
⁴⁰ Department of Psychology, Virginia Commonwealth University, Box 842018, 806W Franklin St, Richmond, VA, 23284, USA.
⁴¹ Amsterdam UMC, VKC Psyche, Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam, The Netherlands.
⁴² Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
⁴³ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaivour, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
⁴⁴ Department of Clinical, Educational and Health Psychology, University College London, London, UK.
⁴⁵ Conway Institute of Biomolecular and Biomedical Sciences, School of Medicine, University College Dublin, Dublin, Ireland.
⁴⁶ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, The Netherlands.

PMID: 36284158
PMCID: PMC10902879
DOI: 10.1038/s41380-022-01793-3

Meta-Analysis

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

Jorim J Tielbeek et al. Mol Psychiatry. 2022 Nov.

. 2022 Nov;27(11):4453-4463.

doi: 10.1038/s41380-022-01793-3. Epub 2022 Oct 25.

Authors

Affiliations

¹ Center for Neurogenomics and Cognitive Research, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands. j.j.tielbeek@vu.nl.
² Center for Neurogenomics and Cognitive Research, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands.
³ Department of Psychology and Neuroscience, Trinity College of Arts and Sciences, Duke University, 2020 West Main Street, Durham, NC, 27705, USA.
⁴ Psychiatric Genetics, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
⁵ Research Unit on Children's Psychosocial Maladjustment, École de psychologie, Université Laval, 2523 Allée des Bibliothèques, Quebec City, QC, G1V 0A6, Canada.
⁶ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Carolina Population Center, University of North Carolina at Chapel Hill, 123 Franklin St, Chapel Hill, NC, 27516, USA.
⁸ Department of Psychology, Faculty of Arts, Psychology, and Theology, Åbo Akademi University, Tuomiokirkontori 3, FI-20500, Turku, Finland.
⁹ MRC Integrative Epidemiology Unit, University of Bristol, Oakfield Road, Bristol, BS8 2BN, UK.
¹⁰ Center for Psychiatric Epidemiology and Psychopathology, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Route de Cery 25, CH-1008, Prilly, Vaud, Switzerland.
¹¹ Department of Psychology, University of Minnesota, 75 E. River Road, Minneapolis, MN, 55455, USA.
¹² Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, DeCrespigny Park, Denmark Hill, London, SE5 8AF, UK.
¹³ Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
¹⁴ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Groteplein 10, 6500 HB, Nijmegen, The Netherlands.
¹⁵ Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.
¹⁶ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
¹⁷ iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000, Aarhus C, Aarhus, Denmark.
¹⁸ Department of Psychology and Logopedics, University of Helsinki, Haartmaninkatu 3, 00014, Helsinki, Finland.
¹⁹ Michigan State University, East Lansing, MI, USA.
²⁰ Dunedin Multidisciplinary Health and Development Research Unit, Department of Psychology, Dunedin, New Zealand.
²¹ Department of Sociology, University of North Carolina at Chapel Hill, CB# 3210, 201 Hamilton Hall, Chapel Hill, NC, 27599, USA.
²² University of Exeter Medical School, University of Exeter, Exeter, UK.
²³ The Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, Birmingham, UK.
²⁴ Genetic Epidemiology, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
²⁵ Department of Neurology, Technical University of Munich, 22 Ismaninger St., 81675, Munich, Germany.
²⁶ Research Unit on Children's Psychosocial Maladjustment, École de criminologie, Université of Montreal, 3150 Rue Jean-Brillant, Montreal, QC, H3T 1N8, Canada.
²⁷ Research Unit on Children's Psychosocial Maladjustment, Département de pédiatrie et de psychologie, University of Montreal, 90 Avenue Vincent d'Indy, Montreal, QC, H2V 2S9, Canada.
²⁸ Research Unit on Children's Psychosocial Maladjustment, CHU Ste-Justine Research Center and Department of Social and Preventive Medicine, University of Montreal, 3175 Chemin de la Côte Ste-Catherine, Montreal, QC, H3T 1C5, Canada.
²⁹ Department of Psychology, Concordia University, 7141 Sherbrooke St. West, Montreal, QC, H4B 1R6, Canada.
³⁰ Research Unit on Children's Psychosocial Maladjustment, Département de psychologie, Université du Québec à Montréal, CP 8888 succursale Centre-ville, Montreal, QC, H3C 3P8, Canada.
³¹ Research Unit on Children's Psychosocial Maladjustment, CHU Sainte-Justine Research Center and University of Montreal, 3175 Chemin de la Côte Ste-Catherine, Montreal, QC, H3T 1C5, Canada.
³² Department of General Practice and Primary Health Care, University of Helsinki, Tukholmankatu 8 B, Helsinki, Finland.
³³ Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
³⁴ School of Criminal Justice, University of Cincinnati, 2840 Bearcat Way, Cincinnati, OH, 45221, USA.
³⁵ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, PO Box 4, (Yliopistonkatu 3), 00014, Helsinki, Finland.
³⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, 171 77, Stockholm, Sweden.
³⁷ Department of Psychology and Population Research Center, University of Texas at Austin, 108 E Dean Keeton Stop #A8000, Austin, TX, 78712, USA.
³⁸ Division of Psychology and Language Sciences, University College London, London, UK.
³⁹ School of Applied Sciences, University of Mississippi, John D. Bower School of Population Health, University of Mississippi Medical Center, 84 Dormitory Row West, University, MS, 38677, USA.
⁴⁰ Department of Psychology, Virginia Commonwealth University, Box 842018, 806W Franklin St, Richmond, VA, 23284, USA.
⁴¹ Amsterdam UMC, VKC Psyche, Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam, The Netherlands.
⁴² Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
⁴³ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaivour, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
⁴⁴ Department of Clinical, Educational and Health Psychology, University College London, London, UK.
⁴⁵ Conway Institute of Biomolecular and Biomedical Sciences, School of Medicine, University College Dublin, Dublin, Ireland.
⁴⁶ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, The Netherlands.

PMID: 36284158
PMCID: PMC10902879
DOI: 10.1038/s41380-022-01793-3

Abstract

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10^-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression r_g = 0.63, insomnia r_g = 0.47), physical health (overweight r_g = 0.19, waist-to-hip ratio r_g = 0.32), smoking (r_g = 0.54), cognitive ability (intelligence r_g = -0.40), educational attainment (years of schooling r_g = -0.46) and reproductive traits (age at first birth r_g = -0.58, father's age at death r_g = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

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Figures

**Fig. 1. SNP-based results from the GWAS meta-analysis (N = 85,359) on broad antisocial behavior.**
a Manhattan plot of the GWAS meta-analysis, showing the negative log10-transformed p value for each SNP. SNP two-sided p values from a linear model were calculated using METAL [24], weighting SNP associations by sample size. b Regional association plot around chromosome 7:114043159 with functional annotations of SNPs in LD of lead SNP rs12536335 (shown in purple). The plot displays GWAS p value plotted against its chromosomal position, where colors represent linkage disequilibrium and r² values with the most significantly associated SNP. c The plot displays CADD scores (Combined Annotation Dependent Depletion) and RegulomeDB scores of these SNPs. d PheWAS plot showing the significance of associations of common variation in the *FOXP2* gene with a wide range of traits and diagnoses based on MAGMA gene-based tests (with Bonferroni-corrected p value: 1.05e–5), as obtained from GWASAtlas (https://atlas.ctglab.nl).

**Fig. 2. Bar charts illustrating the proportion of variance (incremental R², or ΔR²) explained by the PRSs.**
PRSs are shown for broad ASB associated with childhood ASB in the Dunedin Longitudinal Study (A), with externalizing behavior in the E-Risk Study (B), with Conduct Disorder (C) and Oppositional Defiant Disorder (D) in the Philadelphia Neurodevelopmental Cohort Study, with ASB in the Quebec Longitudinal Study of Children’s Development Study (E), and with time-aggregated ASB in the Quebec Newborn Twin Study (F). Asterisks (*) show statistical significance after applying a Bonferroni correction on the 22 tested phenotypes at p < 0.0023.

Fig. 3. Significant genetic correlations of ASB with previously published results of other traits and diseases, computed using cross-trait LD score regression in LDHub, Bonferroni-corrected p value: 0.00068 (bars represent 95% confidence intervals).
For traits with significant correlations with ASB in multiple studies (see Supplementary Table 15), we report the most recent study here.

See this image and copyright information in PMC

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Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

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Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

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