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

Jorim Tielbeek; Emil Uffelmann; Benjamin Williams; Lucia Colodro-Conde; Eloi Gagnon; Travis Mallard; Brandt Levitt; Philip Jansen; Ada Johansson; Hannah Sallis; Giorgio Pistis; Gretschen Saunders; Andrea Allegrini; Kaili Rimfeld; Bettina Konte; Marieke Klein; Annette Hartmann; Jessica Salvatore; Ilja Nolte; Ditte Demontis; Anni Malmberg; Alexandra Burt; Jeanne Savage; Karen Sugden; Richie Poulton; Kathleen Mullan Harris; Scott Vrieze; Matt McGue; William Iacono; Nina Roth Mota; Jonathan Mill; Joana Viana; Brittany Mitchell; Jose Morosoli; Till Andlauer; Isabelle Ouellet-Morin; Richard Tremblay; Sylvana Côté; Jean-Philippe Gouin; Mara Brendgen; Ginette Dionne; Frank Vitaro; Michelle Lupton; Nicholas Martin; COGA Consortium; Spit for Science Working Group; Enrique Castelao; Katri Räikkönen; Johan Eriksson; Jari Lahti; Catharina Hartman; Albertine Oldehinkel; Harold Snieder; Hexuan Liu; Martin Preisig; Alyce Whipp; Eero Vuoksimaa; Yi Lu; Patrik Jern; Dan Rujescu; Ina Giegling; Teemu Palviainen; Jaakko Kaprio; Kathryn Paige Harden; Marcus Munafò; Geneviève Morneau-Vaillancourt; Robert Plomin; Essi Viding; Brian Boutwell; Fazil Aliev; Danielle Dick; Arne Popma; Stephen Faraone; Anders Børglum; Sarah Medland; Barbara Franke; Michel Boivin; Jean-Baptiste Pingault; Jeffrey Glennon; J. C. Barnes; Simon Fisher; Terrie Moffitt; Avshalom Caspi; Tinca Polderman; Danielle Posthuma

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

Jorim Tielbeek^*, Emil Uffelmann, Benjamin Williams, Lucia Colodro-Conde, Eloi Gagnon, Travis Mallard, Brandt Levitt, Philip Jansen, Ada Johansson, Hannah Sallis, Giorgio Pistis, Gretschen Saunders, Andrea Allegrini, Kaili Rimfeld, Bettina Konte, Marieke Klein, Annette Hartmann, Jessica Salvatore, Ilja Nolte, Ditte DemontisAnni Malmberg, Alexandra Burt, Jeanne Savage, Karen Sugden, Richie Poulton, Kathleen Mullan Harris, Scott Vrieze, Matt McGue, William Iacono, Nina Roth Mota, Jonathan Mill, Joana Viana, Brittany Mitchell, Jose Morosoli, Till Andlauer, Isabelle Ouellet-Morin, Richard Tremblay, Sylvana Côté, Jean-Philippe Gouin, Mara Brendgen, Ginette Dionne, Frank Vitaro, Michelle Lupton, Nicholas Martin, COGA Consortium, Spit for Science Working Group, Enrique Castelao, Katri Räikkönen, Johan Eriksson, Jari Lahti, Catharina Hartman, Albertine Oldehinkel, Harold Snieder, Hexuan Liu, Martin Preisig, Alyce Whipp, Eero Vuoksimaa, Yi Lu, Patrik Jern, Dan Rujescu, Ina Giegling, Teemu Palviainen, Jaakko Kaprio, Kathryn Paige Harden, Marcus Munafò, Geneviève Morneau-Vaillancourt, Robert Plomin, Essi Viding, Brian Boutwell, Fazil Aliev, Danielle Dick, Arne Popma, Stephen Faraone, Anders Børglum, Sarah Medland, Barbara Franke, Michel Boivin, Jean-Baptiste Pingault, Jeffrey Glennon, J. C. Barnes, Simon Fisher, Terrie Moffitt, Avshalom Caspi, Tinca Polderman, Danielle Posthuma

^*Corresponding author for this work

Psychology

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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’s age at death rg = −0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

Original language	English
Pages (from-to)	4453-4463
Number of pages	11
Journal	Molecular Psychiatry
Volume	27
Publication status	Published - 2022
MoE publication type	A1 Journal article-refereed

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Tielbeek, J., Uffelmann, E., Williams, B., Colodro-Conde, L., Gagnon, E., Mallard, T., Levitt, B., Jansen, P., Johansson, A., Sallis, H., Pistis, G., Saunders, G., Allegrini, A., Rimfeld, K., Konte, B., Klein, M., Hartmann, A., Salvatore, J., Nolte, I., ... Posthuma, D. (2022). Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis. Molecular Psychiatry, 27, 4453-4463. https://www.nature.com/articles/s41380-022-01793-3

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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. Weidentified 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 = "Jorim Tielbeek and Emil Uffelmann and Benjamin Williams and Lucia Colodro-Conde and Eloi Gagnon and Travis Mallard and Brandt Levitt and Philip Jansen and Ada Johansson and Hannah Sallis and Giorgio Pistis and Gretschen Saunders and Andrea Allegrini and Kaili Rimfeld and Bettina Konte and Marieke Klein and Annette Hartmann and Jessica Salvatore and Ilja Nolte and Ditte Demontis and Anni Malmberg and Alexandra Burt and Jeanne Savage and Karen Sugden and Richie Poulton and {Mullan Harris}, Kathleen and Scott Vrieze and Matt McGue and William Iacono and {Roth Mota}, Nina and Jonathan Mill and Joana Viana and Brittany Mitchell and Jose Morosoli and Till Andlauer and Isabelle Ouellet-Morin and Richard Tremblay and Sylvana C{\^o}t{\'e} and Jean-Philippe Gouin and Mara Brendgen and Ginette Dionne and Frank Vitaro and Michelle Lupton and Nicholas Martin and {COGA Consortium} and {Spit for Science Working Group} and Enrique Castelao and Katri R{\"a}ikk{\"o}nen and Johan Eriksson and Jari Lahti and Catharina Hartman and Albertine Oldehinkel and Harold Snieder and Hexuan Liu and Martin Preisig and Alyce Whipp and Eero Vuoksimaa and Yi Lu and Patrik Jern and Dan Rujescu and Ina Giegling and Teemu Palviainen and Jaakko Kaprio and {Paige Harden}, Kathryn and Marcus Munaf{\`o} and Genevi{\`e}ve Morneau-Vaillancourt and Robert Plomin and Essi Viding and Brian Boutwell and Fazil Aliev and Danielle Dick and Arne Popma and Stephen Faraone and Anders B{\o}rglum and Sarah Medland and Barbara Franke and Michel Boivin and Jean-Baptiste Pingault and Jeffrey Glennon and Barnes, {J. C.} and Simon Fisher and Terrie Moffitt and Avshalom Caspi and Tinca Polderman and Danielle Posthuma",

year = "2022",

language = "English",

volume = "27",

pages = "4453--4463",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature [academic journals on nature.com]",

}

Tielbeek, J, Uffelmann, E, Williams, B, Colodro-Conde, L, Gagnon, E, Mallard, T, Levitt, B, Jansen, P, Johansson, A, Sallis, H, Pistis, G, Saunders, G, Allegrini, A, Rimfeld, K, Konte, B, Klein, M, Hartmann, A, Salvatore, J, Nolte, I, Demontis, D, Malmberg, A, Burt, A, Savage, J, Sugden, K, Poulton, R, Mullan Harris, K, Vrieze, S, McGue, M, Iacono, W, Roth Mota, N, Mill, J, Viana, J, Mitchell, B, Morosoli, J, Andlauer, T, Ouellet-Morin, I, Tremblay, R, Côté, S, Gouin, J-P, Brendgen, M, Dionne, G, Vitaro, F, Lupton, M, Martin, N, COGA Consortium, Spit for Science Working Group, Castelao, E, Räikkönen, K, Eriksson, J, Lahti, J, Hartman, C, Oldehinkel, A, Snieder, H, Liu, H, Preisig, M, Whipp, A, Vuoksimaa, E, Lu, Y, Jern, P, Rujescu, D, Giegling, I, Palviainen, T, Kaprio, J, Paige Harden, K, Munafò, M, Morneau-Vaillancourt, G, Plomin, R, Viding, E, Boutwell, B, Aliev, F, Dick, D, Popma, A, Faraone, S, Børglum, A, Medland, S, Franke, B, Boivin, M, Pingault, J-B, Glennon, J, Barnes, JC, Fisher, S, Moffitt, T, Caspi, A, Polderman, T & Posthuma, D 2022, 'Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis', Molecular Psychiatry, vol. 27, pp. 4453-4463. <https://www.nature.com/articles/s41380-022-01793-3>

TY - JOUR

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

AU - Tielbeek, Jorim

AU - Uffelmann, Emil

AU - Williams, Benjamin

AU - Colodro-Conde, Lucia

AU - Gagnon, Eloi

AU - Mallard, Travis

AU - Levitt, Brandt

AU - Jansen, Philip

AU - Johansson, Ada

AU - Sallis, Hannah

AU - Pistis, Giorgio

AU - Saunders, Gretschen

AU - Allegrini, Andrea

AU - Rimfeld, Kaili

AU - Konte, Bettina

AU - Klein, Marieke

AU - Hartmann, Annette

AU - Salvatore, Jessica

AU - Nolte, Ilja

AU - Demontis, Ditte

AU - Malmberg, Anni

AU - Burt, Alexandra

AU - Savage, Jeanne

AU - Sugden, Karen

AU - Poulton, Richie

AU - Mullan Harris, Kathleen

AU - Vrieze, Scott

AU - McGue, Matt

AU - Iacono, William

AU - Roth Mota, Nina

AU - Mill, Jonathan

AU - Viana, Joana

AU - Mitchell, Brittany

AU - Morosoli, Jose

AU - Andlauer, Till

AU - Ouellet-Morin, Isabelle

AU - Tremblay, Richard

AU - Côté, Sylvana

AU - Gouin, Jean-Philippe

AU - Brendgen, Mara

AU - Dionne, Ginette

AU - Vitaro, Frank

AU - Lupton, Michelle

AU - Martin, Nicholas

AU - COGA Consortium,

AU - Spit for Science Working Group,

AU - Castelao, Enrique

AU - Räikkönen, Katri

AU - Eriksson, Johan

AU - Lahti, Jari

AU - Hartman, Catharina

AU - Oldehinkel, Albertine

AU - Snieder, Harold

AU - Liu, Hexuan

AU - Preisig, Martin

AU - Whipp, Alyce

AU - Vuoksimaa, Eero

AU - Lu, Yi

AU - Jern, Patrik

AU - Rujescu, Dan

AU - Giegling, Ina

AU - Palviainen, Teemu

AU - Kaprio, Jaakko

AU - Paige Harden, Kathryn

AU - Munafò, Marcus

AU - Morneau-Vaillancourt, Geneviève

AU - Plomin, Robert

AU - Viding, Essi

AU - Boutwell, Brian

AU - Aliev, Fazil

AU - Dick, Danielle

AU - Popma, Arne

AU - Faraone, Stephen

AU - Børglum, Anders

AU - Medland, Sarah

AU - Franke, Barbara

AU - Boivin, Michel

AU - Pingault, Jean-Baptiste

AU - Glennon, Jeffrey

AU - Barnes, J. C.

AU - Fisher, Simon

AU - Moffitt, Terrie

AU - Caspi, Avshalom

AU - Polderman, Tinca

AU - Posthuma, Danielle

PY - 2022

Y1 - 2022

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. Weidentified 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. Weidentified 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 - https://www.biorxiv.org/content/10.1101/2021.10.19.462578v1

M3 - Article

SN - 1359-4184

VL - 27

SP - 4453

EP - 4463

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

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

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