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

COGA Consortium; Spit for Science Working Group

doi:10.1038/s41380-022-01793-3

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

COGA Consortium, Spit for Science Working Group

Psychology (Twin Cities)

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4453-4463
Number of pages	11
Journal	Molecular psychiatry
Volume	27
Issue number	11
DOIs	https://doi.org/10.1038/s41380-022-01793-3
State	Published - Nov 2022

Bibliographical note

Funding Information:
GM-V was supported by a Doctoral Research Scholarship from the FRQSC. MB, IO-M, and J-PG are supported by the Canada Research Chair Program. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. ADB and DD were supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (Grant No. 602805, “Aggressotype”) and H2020 Program (Grant No. 667302, “CoCA”), NIMH (1U01MH109514-01. JL, AM, and KR acknowledge the following funders: Academy of Finland, the Signe and Ane Gyllenberg foundation, Juho Vainio foundation, Yrjö Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation and The Finnish Society of Sciences and Letters. DD is supported by NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), R34 AA027347 (Personalized Risk Assessment), R01 AA028064 (Parental Marital Discord, PI: JS), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and by R01 DA050721 (Externalizing Consortium) from the National Institute on Drug Abuse (NIDA). BF, MK, and NRM were also supported by funding from the European Community’s Horizon 2020 Programme (H2020/2014–2020) under grant agreements no. 728018 (Eat2beNICE) and no. 847879 (PRIME). They also received relevant funding from the Netherlands Organization for Scientific Research (NWO) for the Dutch National Science Agenda NeurolabNL project (grant 400-17-602). HMS and MRM are members of the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). This work is also supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. AW has been supported by funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602768 for the ACTION consortium. JK has been supported by the Academy of Finland Academy professorship program (grants 265240 and 263278). LC-C was supported by a QIMR Berghofer Research Fellowship. JJM was supported by a QIMR Berghofer International PhD Scholarship. ML was funded by an NHMRC Boosting Dementia Leadership Fellowship (APP1140441). SEM and NGM were funded by NHMRC investigator grants (APP1172917 and APP1172990). PJ has been supported by Academy of Finland (Grants no. 319403, 284385 and 274521) and the Stiftelsen för Åbo Akademi Foundation. MK was supported by a personal Rubicon grant (no. 45219212) from the Dutch Research Council. Additional acknowledgements for each study cohort are described in Supplementary Table . We acknowledge the work of all members of the Spit for Science Working Group. Spit for Science Director: Danielle M. Dick. Registry management: Kimberly Pedersen, Zoe Neale, Nathaniel Thomas. Data cleaning and management: Amy E. Adkins, Nathaniel Thomas, Zoe Neale, Kimberly Pedersen, Thomas Bannard and Seung B. Cho. Data collection: Amy E. Adkins, Peter Barr, Holly Byers, Erin C. Berenz, Erin Caraway, Seung B. Cho, James S. Clifford, Megan Cooke, Elizabeth Do, Alexis C. Edwards, Neeru Goyal, Laura M. Hack, Lisa J. Halberstadt, Sage Hawn, Sally Kuo, Emily Lasko, Jennifer Lend, Mackenzie Lind, Elizabeth Long, Alexandra Martelli, Jacquelyn L. Meyers, Kerry Mitchell, Ashlee Moore, Arden Moscati, Aashir Nasim, Zoe Neale, Jill Opalesky, Cassie Overstreet, A. Christian Pais, Kimberly Pedersen, Tarah Raldiris, Jessica Salvatore, Jeanne Savage, Rebecca Smith, David Sosnowski, Jinni Su, Nathaniel Thomas, Chloe Walker, Marcie Walsh, Teresa Willoughby, Madison Woodroof and Jia Yan. Genotypical data processing and cleaning: Cuie Sun, Brandon Wormley, Brien Riley, Fazil Aliev, Roseann Peterson and Bradley T. Webb.

Funding Information:
GM-V was supported by a Doctoral Research Scholarship from the FRQSC. MB, IO-M, and J-PG are supported by the Canada Research Chair Program. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. ADB and DD were supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (Grant No. 602805, “Aggressotype”) and H2020 Program (Grant No. 667302, “CoCA”), NIMH (1U01MH109514-01. JL, AM, and KR acknowledge the following funders: Academy of Finland, the Signe and Ane Gyllenberg foundation, Juho Vainio foundation, Yrjö Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation and The Finnish Society of Sciences and Letters. DD is supported by NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), R34 AA027347 (Personalized Risk Assessment), R01 AA028064 (Parental Marital Discord, PI: JS), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and by R01 DA050721 (Externalizing Consortium) from the National Institute on Drug Abuse (NIDA). BF, MK, and NRM were also supported by funding from the European Community’s Horizon 2020 Programme (H2020/2014–2020) under grant agreements no. 728018 (Eat2beNICE) and no. 847879 (PRIME). They also received relevant funding from the Netherlands Organization for Scientific Research (NWO) for the Dutch National Science Agenda NeurolabNL project (grant 400-17-602). HMS and MRM are members of the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). This work is also supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. AW has been supported by funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602768 for the ACTION consortium. JK has been supported by the Academy of Finland Academy professorship program (grants 265240 and 263278). LC-C was supported by a QIMR Berghofer Research Fellowship. JJM was supported by a QIMR Berghofer International PhD Scholarship. ML was funded by an NHMRC Boosting Dementia Leadership Fellowship (APP1140441). SEM and NGM were funded by NHMRC investigator grants (APP1172917 and APP1172990). PJ has been supported by Academy of Finland (Grants no. 319403, 284385 and 274521) and the Stiftelsen för Åbo Akademi Foundation. MK was supported by a personal Rubicon grant (no. 45219212) from the Dutch Research Council. Additional acknowledgements for each study cohort are described in Supplementary Table 1. We acknowledge the work of all members of the Spit for Science Working Group. Spit for Science Director: Danielle M. Dick. Registry management: Kimberly Pedersen, Zoe Neale, Nathaniel Thomas. Data cleaning and management: Amy E. Adkins, Nathaniel Thomas, Zoe Neale, Kimberly Pedersen, Thomas Bannard and Seung B. Cho. Data collection: Amy E. Adkins, Peter Barr, Holly Byers, Erin C. Berenz, Erin Caraway, Seung B. Cho, James S. Clifford, Megan Cooke, Elizabeth Do, Alexis C. Edwards, Neeru Goyal, Laura M. Hack, Lisa J. Halberstadt, Sage Hawn, Sally Kuo, Emily Lasko, Jennifer Lend, Mackenzie Lind, Elizabeth Long, Alexandra Martelli, Jacquelyn L. Meyers, Kerry Mitchell, Ashlee Moore, Arden Moscati, Aashir Nasim, Zoe Neale, Jill Opalesky, Cassie Overstreet, A. Christian Pais, Kimberly Pedersen, Tarah Raldiris, Jessica Salvatore, Jeanne Savage, Rebecca Smith, David Sosnowski, Jinni Su, Nathaniel Thomas, Chloe Walker, Marcie Walsh, Teresa Willoughby, Madison Woodroof and Jia Yan. Genotypical data processing and cleaning: Cuie Sun, Brandon Wormley, Brien Riley, Fazil Aliev, Roseann Peterson and Bradley T. Webb.

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@article{fb9703bf9ba347cc9f92c29b0b9389bd,

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

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 rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = −0.40), educational attainment (years of schooling rg = −0.46) and reproductive traits (age at first birth rg = −0.58, father{\textquoteright}s age at death rg = −0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.",

author = "{COGA Consortium} and {Spit for Science Working Group} and Tielbeek, {Jorim J.} and Emil Uffelmann and Williams, {Benjamin S.} and Luc{\'i}a Colodro-Conde and {\'E}loi Gagnon and Mallard, {Travis T.} and Levitt, {Brandt E.} and Jansen, {Philip R.} and Ada Johansson and Sallis, {Hannah M.} and Giorgio Pistis and Saunders, {Gretchen R.B.} and Allegrini, {Andrea G.} and Kaili Rimfeld and Bettina Konte and Marieke Klein and Hartmann, {Annette M.} and Salvatore, {Jessica E.} and Nolte, {Ilja M.} and Ditte Demontis and Malmberg, {Anni L.K.} and Burt, {S. Alexandra} and Savage, {Jeanne E.} and Karen Sugden and Richie Poulton and Harris, {Kathleen Mullan} and Scott Vrieze and Matt McGue and Iacono, {William G.} and Mota, {Nina Roth} and Jonathan Mill and Viana, {Joana F.} and Mitchell, {Brittany L.} and Morosoli, {Jose J.} and Andlauer, {Till F.M.} and Isabelle Ouellet-Morin and Tremblay, {Richard E.} and C{\^o}t{\'e}, {Sylvana M.} and Gouin, {Jean Philippe} and Brendgen, {Mara R.} and Ginette Dionne and Frank Vitaro and Lupton, {Michelle K.} and Martin, {Nicholas G.} and Bernice Porjesz and Victor Hesselbrock and Tatiana Foroud and Arpana Agrawal and Edenberg, {Howard J.} and Yunlong Liu",

note = "Funding Information: GM-V was supported by a Doctoral Research Scholarship from the FRQSC. MB, IO-M, and J-PG are supported by the Canada Research Chair Program. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. ADB and DD were supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (Grant No. 602805, “Aggressotype”) and H2020 Program (Grant No. 667302, “CoCA”), NIMH (1U01MH109514-01. JL, AM, and KR acknowledge the following funders: Academy of Finland, the Signe and Ane Gyllenberg foundation, Juho Vainio foundation, Yrj{\"o} Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation and The Finnish Society of Sciences and Letters. DD is supported by NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), R34 AA027347 (Personalized Risk Assessment), R01 AA028064 (Parental Marital Discord, PI: JS), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and by R01 DA050721 (Externalizing Consortium) from the National Institute on Drug Abuse (NIDA). BF, MK, and NRM were also supported by funding from the European Community{\textquoteright}s Horizon 2020 Programme (H2020/2014–2020) under grant agreements no. 728018 (Eat2beNICE) and no. 847879 (PRIME). They also received relevant funding from the Netherlands Organization for Scientific Research (NWO) for the Dutch National Science Agenda NeurolabNL project (grant 400-17-602). HMS and MRM are members of the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). This work is also supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. AW has been supported by funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602768 for the ACTION consortium. JK has been supported by the Academy of Finland Academy professorship program (grants 265240 and 263278). LC-C was supported by a QIMR Berghofer Research Fellowship. JJM was supported by a QIMR Berghofer International PhD Scholarship. ML was funded by an NHMRC Boosting Dementia Leadership Fellowship (APP1140441). SEM and NGM were funded by NHMRC investigator grants (APP1172917 and APP1172990). PJ has been supported by Academy of Finland (Grants no. 319403, 284385 and 274521) and the Stiftelsen f{\"o}r {\AA}bo Akademi Foundation. MK was supported by a personal Rubicon grant (no. 45219212) from the Dutch Research Council. Additional acknowledgements for each study cohort are described in Supplementary Table . We acknowledge the work of all members of the Spit for Science Working Group. Spit for Science Director: Danielle M. Dick. Registry management: Kimberly Pedersen, Zoe Neale, Nathaniel Thomas. Data cleaning and management: Amy E. Adkins, Nathaniel Thomas, Zoe Neale, Kimberly Pedersen, Thomas Bannard and Seung B. Cho. Data collection: Amy E. Adkins, Peter Barr, Holly Byers, Erin C. Berenz, Erin Caraway, Seung B. Cho, James S. Clifford, Megan Cooke, Elizabeth Do, Alexis C. Edwards, Neeru Goyal, Laura M. Hack, Lisa J. Halberstadt, Sage Hawn, Sally Kuo, Emily Lasko, Jennifer Lend, Mackenzie Lind, Elizabeth Long, Alexandra Martelli, Jacquelyn L. Meyers, Kerry Mitchell, Ashlee Moore, Arden Moscati, Aashir Nasim, Zoe Neale, Jill Opalesky, Cassie Overstreet, A. Christian Pais, Kimberly Pedersen, Tarah Raldiris, Jessica Salvatore, Jeanne Savage, Rebecca Smith, David Sosnowski, Jinni Su, Nathaniel Thomas, Chloe Walker, Marcie Walsh, Teresa Willoughby, Madison Woodroof and Jia Yan. Genotypical data processing and cleaning: Cuie Sun, Brandon Wormley, Brien Riley, Fazil Aliev, Roseann Peterson and Bradley T. Webb. Funding Information: GM-V was supported by a Doctoral Research Scholarship from the FRQSC. MB, IO-M, and J-PG are supported by the Canada Research Chair Program. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. ADB and DD were supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (Grant No. 602805, “Aggressotype”) and H2020 Program (Grant No. 667302, “CoCA”), NIMH (1U01MH109514-01. JL, AM, and KR acknowledge the following funders: Academy of Finland, the Signe and Ane Gyllenberg foundation, Juho Vainio foundation, Yrj{\"o} Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation and The Finnish Society of Sciences and Letters. DD is supported by NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), R34 AA027347 (Personalized Risk Assessment), R01 AA028064 (Parental Marital Discord, PI: JS), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and by R01 DA050721 (Externalizing Consortium) from the National Institute on Drug Abuse (NIDA). BF, MK, and NRM were also supported by funding from the European Community{\textquoteright}s Horizon 2020 Programme (H2020/2014–2020) under grant agreements no. 728018 (Eat2beNICE) and no. 847879 (PRIME). They also received relevant funding from the Netherlands Organization for Scientific Research (NWO) for the Dutch National Science Agenda NeurolabNL project (grant 400-17-602). HMS and MRM are members of the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). This work is also supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. AW has been supported by funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602768 for the ACTION consortium. JK has been supported by the Academy of Finland Academy professorship program (grants 265240 and 263278). LC-C was supported by a QIMR Berghofer Research Fellowship. JJM was supported by a QIMR Berghofer International PhD Scholarship. ML was funded by an NHMRC Boosting Dementia Leadership Fellowship (APP1140441). SEM and NGM were funded by NHMRC investigator grants (APP1172917 and APP1172990). PJ has been supported by Academy of Finland (Grants no. 319403, 284385 and 274521) and the Stiftelsen f{\"o}r {\AA}bo Akademi Foundation. MK was supported by a personal Rubicon grant (no. 45219212) from the Dutch Research Council. Additional acknowledgements for each study cohort are described in Supplementary Table 1. We acknowledge the work of all members of the Spit for Science Working Group. Spit for Science Director: Danielle M. Dick. Registry management: Kimberly Pedersen, Zoe Neale, Nathaniel Thomas. Data cleaning and management: Amy E. Adkins, Nathaniel Thomas, Zoe Neale, Kimberly Pedersen, Thomas Bannard and Seung B. Cho. Data collection: Amy E. Adkins, Peter Barr, Holly Byers, Erin C. Berenz, Erin Caraway, Seung B. Cho, James S. Clifford, Megan Cooke, Elizabeth Do, Alexis C. Edwards, Neeru Goyal, Laura M. Hack, Lisa J. Halberstadt, Sage Hawn, Sally Kuo, Emily Lasko, Jennifer Lend, Mackenzie Lind, Elizabeth Long, Alexandra Martelli, Jacquelyn L. Meyers, Kerry Mitchell, Ashlee Moore, Arden Moscati, Aashir Nasim, Zoe Neale, Jill Opalesky, Cassie Overstreet, A. Christian Pais, Kimberly Pedersen, Tarah Raldiris, Jessica Salvatore, Jeanne Savage, Rebecca Smith, David Sosnowski, Jinni Su, Nathaniel Thomas, Chloe Walker, Marcie Walsh, Teresa Willoughby, Madison Woodroof and Jia Yan. Genotypical data processing and cleaning: Cuie Sun, Brandon Wormley, Brien Riley, Fazil Aliev, Roseann Peterson and Bradley T. Webb. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = nov,

doi = "10.1038/s41380-022-01793-3",

language = "English (US)",

volume = "27",

pages = "4453--4463",

journal = "Molecular psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "11",

}

TY - JOUR

T1 - Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis

AU - COGA Consortium

AU - Spit for Science Working Group

AU - Tielbeek, Jorim J.

AU - Uffelmann, Emil

AU - Williams, Benjamin S.

AU - Colodro-Conde, Lucía

AU - Gagnon, Éloi

AU - Mallard, Travis T.

AU - Levitt, Brandt E.

AU - Jansen, Philip R.

AU - Johansson, Ada

AU - Sallis, Hannah M.

AU - Pistis, Giorgio

AU - Saunders, Gretchen R.B.

AU - Allegrini, Andrea G.

AU - Rimfeld, Kaili

AU - Konte, Bettina

AU - Klein, Marieke

AU - Hartmann, Annette M.

AU - Salvatore, Jessica E.

AU - Nolte, Ilja M.

AU - Demontis, Ditte

AU - Malmberg, Anni L.K.

AU - Burt, S. Alexandra

AU - Savage, Jeanne E.

AU - Sugden, Karen

AU - Poulton, Richie

AU - Harris, Kathleen Mullan

AU - Vrieze, Scott

AU - McGue, Matt

AU - Iacono, William G.

AU - Mota, Nina Roth

AU - Mill, Jonathan

AU - Viana, Joana F.

AU - Mitchell, Brittany L.

AU - Morosoli, Jose J.

AU - Andlauer, Till F.M.

AU - Ouellet-Morin, Isabelle

AU - Tremblay, Richard E.

AU - Côté, Sylvana M.

AU - Gouin, Jean Philippe

AU - Brendgen, Mara R.

AU - Dionne, Ginette

AU - Vitaro, Frank

AU - Lupton, Michelle K.

AU - Martin, Nicholas G.

AU - Porjesz, Bernice

AU - Hesselbrock, Victor

AU - Foroud, Tatiana

AU - Agrawal, Arpana

AU - Edenberg, Howard J.

AU - Liu, Yunlong

N1 - Funding Information: GM-V was supported by a Doctoral Research Scholarship from the FRQSC. MB, IO-M, and J-PG are supported by the Canada Research Chair Program. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. ADB and DD were supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (Grant No. 602805, “Aggressotype”) and H2020 Program (Grant No. 667302, “CoCA”), NIMH (1U01MH109514-01. JL, AM, and KR acknowledge the following funders: Academy of Finland, the Signe and Ane Gyllenberg foundation, Juho Vainio foundation, Yrjö Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation and The Finnish Society of Sciences and Letters. DD is supported by NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), R34 AA027347 (Personalized Risk Assessment), R01 AA028064 (Parental Marital Discord, PI: JS), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and by R01 DA050721 (Externalizing Consortium) from the National Institute on Drug Abuse (NIDA). BF, MK, and NRM were also supported by funding from the European Community’s Horizon 2020 Programme (H2020/2014–2020) under grant agreements no. 728018 (Eat2beNICE) and no. 847879 (PRIME). They also received relevant funding from the Netherlands Organization for Scientific Research (NWO) for the Dutch National Science Agenda NeurolabNL project (grant 400-17-602). HMS and MRM are members of the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). This work is also supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. AW has been supported by funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602768 for the ACTION consortium. JK has been supported by the Academy of Finland Academy professorship program (grants 265240 and 263278). LC-C was supported by a QIMR Berghofer Research Fellowship. JJM was supported by a QIMR Berghofer International PhD Scholarship. ML was funded by an NHMRC Boosting Dementia Leadership Fellowship (APP1140441). SEM and NGM were funded by NHMRC investigator grants (APP1172917 and APP1172990). PJ has been supported by Academy of Finland (Grants no. 319403, 284385 and 274521) and the Stiftelsen för Åbo Akademi Foundation. MK was supported by a personal Rubicon grant (no. 45219212) from the Dutch Research Council. Additional acknowledgements for each study cohort are described in Supplementary Table . We acknowledge the work of all members of the Spit for Science Working Group. Spit for Science Director: Danielle M. Dick. Registry management: Kimberly Pedersen, Zoe Neale, Nathaniel Thomas. Data cleaning and management: Amy E. Adkins, Nathaniel Thomas, Zoe Neale, Kimberly Pedersen, Thomas Bannard and Seung B. Cho. Data collection: Amy E. Adkins, Peter Barr, Holly Byers, Erin C. Berenz, Erin Caraway, Seung B. Cho, James S. Clifford, Megan Cooke, Elizabeth Do, Alexis C. Edwards, Neeru Goyal, Laura M. Hack, Lisa J. Halberstadt, Sage Hawn, Sally Kuo, Emily Lasko, Jennifer Lend, Mackenzie Lind, Elizabeth Long, Alexandra Martelli, Jacquelyn L. Meyers, Kerry Mitchell, Ashlee Moore, Arden Moscati, Aashir Nasim, Zoe Neale, Jill Opalesky, Cassie Overstreet, A. Christian Pais, Kimberly Pedersen, Tarah Raldiris, Jessica Salvatore, Jeanne Savage, Rebecca Smith, David Sosnowski, Jinni Su, Nathaniel Thomas, Chloe Walker, Marcie Walsh, Teresa Willoughby, Madison Woodroof and Jia Yan. Genotypical data processing and cleaning: Cuie Sun, Brandon Wormley, Brien Riley, Fazil Aliev, Roseann Peterson and Bradley T. Webb. Funding Information: GM-V was supported by a Doctoral Research Scholarship from the FRQSC. MB, IO-M, and J-PG are supported by the Canada Research Chair Program. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. ADB and DD were supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (Grant No. 602805, “Aggressotype”) and H2020 Program (Grant No. 667302, “CoCA”), NIMH (1U01MH109514-01. JL, AM, and KR acknowledge the following funders: Academy of Finland, the Signe and Ane Gyllenberg foundation, Juho Vainio foundation, Yrjö Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation and The Finnish Society of Sciences and Letters. DD is supported by NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), R34 AA027347 (Personalized Risk Assessment), R01 AA028064 (Parental Marital Discord, PI: JS), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and by R01 DA050721 (Externalizing Consortium) from the National Institute on Drug Abuse (NIDA). BF, MK, and NRM were also supported by funding from the European Community’s Horizon 2020 Programme (H2020/2014–2020) under grant agreements no. 728018 (Eat2beNICE) and no. 847879 (PRIME). They also received relevant funding from the Netherlands Organization for Scientific Research (NWO) for the Dutch National Science Agenda NeurolabNL project (grant 400-17-602). HMS and MRM are members of the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). This work is also supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. AW has been supported by funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602768 for the ACTION consortium. JK has been supported by the Academy of Finland Academy professorship program (grants 265240 and 263278). LC-C was supported by a QIMR Berghofer Research Fellowship. JJM was supported by a QIMR Berghofer International PhD Scholarship. ML was funded by an NHMRC Boosting Dementia Leadership Fellowship (APP1140441). SEM and NGM were funded by NHMRC investigator grants (APP1172917 and APP1172990). PJ has been supported by Academy of Finland (Grants no. 319403, 284385 and 274521) and the Stiftelsen för Åbo Akademi Foundation. MK was supported by a personal Rubicon grant (no. 45219212) from the Dutch Research Council. Additional acknowledgements for each study cohort are described in Supplementary Table 1. We acknowledge the work of all members of the Spit for Science Working Group. Spit for Science Director: Danielle M. Dick. Registry management: Kimberly Pedersen, Zoe Neale, Nathaniel Thomas. Data cleaning and management: Amy E. Adkins, Nathaniel Thomas, Zoe Neale, Kimberly Pedersen, Thomas Bannard and Seung B. Cho. Data collection: Amy E. Adkins, Peter Barr, Holly Byers, Erin C. Berenz, Erin Caraway, Seung B. Cho, James S. Clifford, Megan Cooke, Elizabeth Do, Alexis C. Edwards, Neeru Goyal, Laura M. Hack, Lisa J. Halberstadt, Sage Hawn, Sally Kuo, Emily Lasko, Jennifer Lend, Mackenzie Lind, Elizabeth Long, Alexandra Martelli, Jacquelyn L. Meyers, Kerry Mitchell, Ashlee Moore, Arden Moscati, Aashir Nasim, Zoe Neale, Jill Opalesky, Cassie Overstreet, A. Christian Pais, Kimberly Pedersen, Tarah Raldiris, Jessica Salvatore, Jeanne Savage, Rebecca Smith, David Sosnowski, Jinni Su, Nathaniel Thomas, Chloe Walker, Marcie Walsh, Teresa Willoughby, Madison Woodroof and Jia Yan. Genotypical data processing and cleaning: Cuie Sun, Brandon Wormley, Brien Riley, Fazil Aliev, Roseann Peterson and Bradley T. Webb. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/11

Y1 - 2022/11

N2 - 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 rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = −0.40), educational attainment (years of schooling rg = −0.46) and reproductive traits (age at first birth rg = −0.58, father’s age at death rg = −0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

AB - 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 rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = −0.40), educational attainment (years of schooling rg = −0.46) and reproductive traits (age at first birth rg = −0.58, father’s age at death rg = −0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

UR - http://www.scopus.com/inward/record.url?scp=85141068730&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85141068730&partnerID=8YFLogxK

U2 - 10.1038/s41380-022-01793-3

DO - 10.1038/s41380-022-01793-3

M3 - Article

C2 - 36284158

AN - SCOPUS:85141068730

SN - 1359-4184

VL - 27

SP - 4453

EP - 4463

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 11

ER -

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

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