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

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

Biostatistics

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

101 Citations (SciVal)

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 formeta-analysis from March 1, 2014, toMay 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
DOIs	https://doi.org/10.1001/jamapsychiatry.2017.3069
State	Published - Dec 2017

Bibliographical note

Funding Information:
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 Information:
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.

Publisher Copyright:
© 2017 American Medical Association. All rights reserved.

ASJC Scopus subject areas

Psychiatry and Mental health

UN SDGs

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

Access to Document

10.1001/jamapsychiatry.2017.3069

Cite this

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., ... Posthuma, D. (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

@article{9536690d20d542d2b76b488ac8857861,

title = "Genome-wide association studies of a broad spectrum of antisocial behavior",

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 formeta-analysis from March 1, 2014, toMay 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.",

author = "Tielbeek, {Jorim J.} and Ada Johansson and Polderman, {Tinca J.C.} and Rautiainen, {Marja Riitta} 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",

note = "Funding Information: 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 Linn{\'e}r, 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 Information: 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. Publisher Copyright: {\textcopyright} 2017 American Medical Association. All rights reserved.",

year = "2017",

month = dec,

doi = "10.1001/jamapsychiatry.2017.3069",

language = "English",

volume = "74",

pages = "1242--1250",

number = "12",

}

Tielbeek, JJ, Johansson, A, Polderman, TJC, Rautiainen, MR, 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 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

N1 - Funding Information: 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 Information: 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. Publisher Copyright: © 2017 American Medical Association. All rights reserved.

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 formeta-analysis from March 1, 2014, toMay 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 formeta-analysis from March 1, 2014, toMay 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.

UR - http://www.scopus.com/inward/record.url?scp=85038248965&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038248965&partnerID=8YFLogxK

U2 - 10.1001/jamapsychiatry.2017.3069

DO - 10.1001/jamapsychiatry.2017.3069

M3 - Article

C2 - 28979981

AN - SCOPUS:85038248965

VL - 74

SP - 1242

EP - 1250

IS - 12

ER -

Genome-wide association studies of a broad spectrum of antisocial behavior

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this