Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior

Jorim J Tielbeek; Ada Johansson; Tinca J C Polderman; Marja-Riitta Rautiainen; Philip Jansen; Michelle Taylor; Xiaoran Tong; Qing Lu; Alexandra S Burt; Henning Tiemeier; Essi Viding; Robert Plomin; Nicholas G Martin; Andrew C Heath; Pamela A F Madden; Grant Montgomery; Kevin M Beaver; Irwin Waldman; Joel Gelernter; Henry R Kranzler; Lindsay A Farrer; John R B Perry; Marcus Munafò; Devon LoParo; Tiina Paunio; Jari Tiihonen; Sabine E Mous; Irene Pappa; Christiaan de Leeuw; Kyoko Watanabe; Anke R Hammerschlag; Jessica E Salvatore; Fazil Aliev; Tim B Bigdeli; Danielle Dick; Stephen V Faraone; Arne Popma; Sarah E Medland; Danielle Posthuma; Broad Antisocial Behavior Consortium collaborators

doi:10.1001/jamapsychiatry.2017.3069

Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior

Jorim J Tielbeek, Ada Johansson, Tinca J C Polderman, Marja-Riitta Rautiainen, Philip Jansen, Michelle Taylor, Xiaoran Tong, Qing Lu, Alexandra S Burt, Henning Tiemeier, Essi Viding, Robert Plomin, Nicholas G Martin, Andrew C Heath, Pamela A F Madden, Grant Montgomery, Kevin M Beaver, Irwin Waldman, Joel Gelernter, Henry R KranzlerLindsay A Farrer, John R B Perry, Marcus Munafò, Devon LoParo, Tiina Paunio, Jari Tiihonen, Sabine E Mous, Irene Pappa, Christiaan de Leeuw, Kyoko Watanabe, Anke R Hammerschlag, Jessica E Salvatore, Fazil Aliev, Tim B Bigdeli, Danielle Dick, Stephen V Faraone, Arne Popma, Sarah E Medland, Danielle Posthuma, Broad Antisocial Behavior Consortium collaborators

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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.

Original language	English
Pages (from-to)	1242-1250
Number of pages	9
Journal	JAMA Psychiatry
Volume	74
Issue number	12
Early online date	4 Oct 2017
DOIs	https://doi.org/10.1001/jamapsychiatry.2017.3069
Publication status	Published - Dec 2017

Funding

Additional Contributions: Meta-analyses and statistical analyses for the Twins Early Development Study were performed on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by grant NWO 480-05-003 from the Netherlands Organization for Scientific Research. Dr Mous was funded by National Health and Medical Research Council Senior Research Fellowship APP1103623. Gabriel Cellular Partida, PhD, University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia, provided the script for the Miami plot; J.C. Barnes, PhD, School of Criminal Justice, University of Cincinnati, Cincinnati, Ohio, and Philipp Koellinger, PhD, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands, provided helpful comments on the manuscript; and Richard Karlsson Linnér, MSc, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands, provided advice on statistical power. None of these individuals were compensated for their work. This research was facilitated by the Social Science Genetic Association Consortium. We thank the individuals who participated in the studies. A full list of cohort acknowledgments is provided in the Supplement. Funding/Support: This project was funded by grants 406-12-131 and 453-14-005 from the Netherlands Organization for Scientific Research, award K01DA033346 from the National Institute on Drug Abuse, an F32AA022269 fellowship, grant K01AA024152 from the National Institutes of Health, the Foundation “De Drie Lichten” in the Netherlands, the Waldemar von Frenckell Foundation, the Finnish Cultural Foundation, the Finnish Ministry of Health and Social Affairs through the development fund for Niuvanniemi Hospital, Kuopio, Finland, and the Society of Swedish Literature in Finland.

Funders	Funder number
National Institutes of Health
National Institute on Drug Abuse	F32AA022269, R01DA043501, K01AA024152, K01DA033346
National Health and Medical Research Council	APP1103623
Suomen Kulttuurirahasto
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Sosiaali- ja Terveysministeriö
Svenska Litteratursällskapet i Finland
Waldemar von Frenckells Stiftelse

Keywords

Adolescent
Adult
Antisocial Personality Disorder
Child
Conduct Disorder
Environment
Female
Finland
Genetic Variation
Genome-Wide Association Study
Humans
Journal Article
Male
Middle Aged
Multifactorial Inheritance
Sex Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1001/jamapsychiatry.2017.3069

jamapsychiatry_Tielbeek_2017_oi_170075_Genome-Wide Association Studies of a Broad Spectrum of Antisocial BehaviorFinal published version, 428 KBLicence: Article 25fa Dutch Copyright Act

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Tielbeek, J. J., Johansson, A., Polderman, T. J. C., Rautiainen, M.-R., Jansen, P., Taylor, M., Tong, X., Lu, Q., Burt, A. S., Tiemeier, H., Viding, E., Plomin, R., Martin, N. G., Heath, A. C., Madden, P. A. F., Montgomery, G., Beaver, K. M., Waldman, I., Gelernter, J., ... Broad Antisocial Behavior Consortium collaborators (2017). Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior. JAMA Psychiatry, 74(12), 1242-1250. https://doi.org/10.1001/jamapsychiatry.2017.3069

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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.",

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author = "Tielbeek, {Jorim J} and Ada Johansson and Polderman, {Tinca J C} and Marja-Riitta Rautiainen and Philip Jansen and Michelle Taylor and Xiaoran Tong and Qing Lu and Burt, {Alexandra S} and Henning Tiemeier and Essi Viding and Robert Plomin and Martin, {Nicholas G} and Heath, {Andrew C} and Madden, {Pamela A F} and Grant Montgomery and Beaver, {Kevin M} and Irwin Waldman and Joel Gelernter and Kranzler, {Henry R} and Farrer, {Lindsay A} and Perry, {John R B} and Marcus Munaf{\`o} and Devon LoParo and Tiina Paunio and Jari Tiihonen and Mous, {Sabine E} and Irene Pappa and {de Leeuw}, Christiaan and Kyoko Watanabe and Hammerschlag, {Anke R} and Salvatore, {Jessica E} and Fazil Aliev and Bigdeli, {Tim B} and Danielle Dick and Faraone, {Stephen V} and Arne Popma and Medland, {Sarah E} and Danielle Posthuma and {Broad Antisocial Behavior Consortium collaborators}",

year = "2017",

month = dec,

doi = "10.1001/jamapsychiatry.2017.3069",

language = "English",

volume = "74",

pages = "1242--1250",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "12",

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Tielbeek, JJ, Johansson, A, Polderman, TJC, Rautiainen, M-R, Jansen, P, Taylor, M, Tong, X, Lu, Q, Burt, AS, Tiemeier, H, Viding, E, Plomin, R, Martin, NG, Heath, AC, Madden, PAF, Montgomery, G, Beaver, KM, Waldman, I, Gelernter, J, Kranzler, HR, Farrer, LA, Perry, JRB, Munafò, M, LoParo, D, Paunio, T, Tiihonen, J, Mous, SE, Pappa, I, de Leeuw, C, Watanabe, K, Hammerschlag, AR, Salvatore, JE, Aliev, F, Bigdeli, TB, Dick, D, Faraone, SV, Popma, A, Medland, SE, Posthuma, D & Broad Antisocial Behavior Consortium collaborators 2017, 'Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior', JAMA Psychiatry, vol. 74, no. 12, pp. 1242-1250. https://doi.org/10.1001/jamapsychiatry.2017.3069

TY - JOUR

T1 - Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior

AU - Tielbeek, Jorim J

AU - Johansson, Ada

AU - Polderman, Tinca J C

AU - Rautiainen, Marja-Riitta

AU - Jansen, Philip

AU - Taylor, Michelle

AU - Tong, Xiaoran

AU - Lu, Qing

AU - Burt, Alexandra S

AU - Tiemeier, Henning

AU - Viding, Essi

AU - Plomin, Robert

AU - Martin, Nicholas G

AU - Heath, Andrew C

AU - Madden, Pamela A F

AU - Montgomery, Grant

AU - Beaver, Kevin M

AU - Waldman, Irwin

AU - Gelernter, Joel

AU - Kranzler, Henry R

AU - Farrer, Lindsay A

AU - Perry, John R B

AU - Munafò, Marcus

AU - LoParo, Devon

AU - Paunio, Tiina

AU - Tiihonen, Jari

AU - Mous, Sabine E

AU - Pappa, Irene

AU - de Leeuw, Christiaan

AU - Watanabe, Kyoko

AU - Hammerschlag, Anke R

AU - Salvatore, Jessica E

AU - Aliev, Fazil

AU - Bigdeli, Tim B

AU - Dick, Danielle

AU - Faraone, Stephen V

AU - Popma, Arne

AU - Medland, Sarah E

AU - Posthuma, Danielle

AU - Broad Antisocial Behavior Consortium collaborators

PY - 2017/12

Y1 - 2017/12

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Antisocial Personality Disorder

KW - Child

KW - Conduct Disorder

KW - Environment

KW - Female

KW - Finland

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Journal Article

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Sex Factors

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Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior

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