Abstract
Aggression and callous, uncaring, and unemotional (CU) traits are clinically related behavioral constructs caused by genetic and environmental factors. We performed polygenic risk score (PRS) analyses to investigate shared genetic etiology between aggression and these three CU-traits. Furthermore, we studied interactions of PRS with smoking during pregnancy and childhood life events in relation to CU-traits. Summary statistics for the base phenotype were derived from the EAGLE-consortium genome-wide association study of children’s aggressive behavior and were used to calculate individual-level genome-wide and gene-set PRS in the NeuroIMAGE target-sample. Target phenotypes were ‘callousness’, ‘uncaring’, and ‘unemotional’ sumscores of the Inventory of Callous-Unemotional traits. A total of 779 subjects and 1,192,414 single-nucleotide polymorphisms were available for PRS-analyses. Gene-sets comprised serotonergic, dopaminergic, glutamatergic, and neuroendocrine signaling pathways. Genome-wide PRS showed evidence of association with uncaring scores (explaining up to 1.59% of variance; self-contained Q = 0.0306, competitive-P = 0.0015). Dopaminergic, glutamatergic, and neuroendocrine PRS showed evidence of association with unemotional scores (explaining up to 1.33, 2.00, and 1.20% of variance respectively; self-contained Q-values 0.037, 0.0115, and 0.0473 respectively, competitive-P-values 0.0029, 0.0002, and 0.0045 respectively). Smoking during pregnancy related to callousness scores while childhood life events related to both callousness and unemotionality. Moreover, dopaminergic PRS appeared to interact with childhood life events in relation to unemotional scores. Our study provides evidence suggesting shared genetic etiology between aggressive behavior and uncaring, and unemotional CU-traits in children. Gene-set PRS confirmed involvement of shared glutamatergic, dopaminergic, and neuroendocrine genetic variation in aggression and CU-traits. Replication of current findings is needed.
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References
Blair RJR, Leibenluft E, Pine DS. Conduct disorder and callous–unemotional traits in youth. N Engl J Med. 2014;371:2207–16.
Waltes R, Chiocchetti AG, Freitag CM. The neurobiological basis of human aggression: a review on genetic and epigenetic mechanisms. Am J Med Genet Part B Neuropsychiatr Genet. 2016;171:650–75.
Olsson M. DSM diagnosis of conduct disorder (CD)-a review. Nord J Psychiatry. 2009;63:102–12.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
Herpers PCM, Klip H, Rommelse NNJ, Greven CU, Buitelaar JK. Associations between high callous–unemotional traits and quality of life across youths with non-conduct disorder diagnoses. Eur Child Adolesc Psychiatry. 2016;25:547–55.
Kempes M, Matthys W, De Vries H, Van Engeland H. Reactive and proactive aggression in children. A review of theory, findings and the relevance for child and adolescent psychiatry. Eur Child Adolesc Psychiatry. 2005;14:11–9.
Veroude K, Zhang-James Y, Fernàndez-Castillo N, Bakker MJ, Cormand B, Faraone SV. Genetics of aggressive behavior: an overview. Am J Med Genet B Neuropsychiatr Genet. 2016;171:3–43.
Pappa I, St Pourcain B, Benke K, Cavadino A, Hakulinen C, Nivard MG, et al. A genome-wide approach to children’s aggressive behavior: the EAGLE consortium. Am J Med Genet B Neuropsychiatr Genet. 2016;171:562–72.
Tielbeek JJ, Johansson A, Polderman TJC, Rautiainen M-R, Jansen P, Taylor M, et al. Genome-wide association studies of a broad spectrum of antisocial behavior. JAMA Psychiatry. 2017;74:1242–50.
Rautiainen M, Paunio T, Repo-Tiihonen E, Virkkunen M, Ollila H, Sulkava S, et al. Genome-wide association study of antisocial personality disorder. Transl Psychiatry 2016;6:e883.
Andlauer T, Müller-Myhsok B, Ripke S. Statistical genetics: genome-wide studies. In: Schulze T, McMahon F, editors. Psychiatric genetics: a primer for clinical and basic scientists. 1st ed. Oxford University Press; 2018. p. 57–69.
Purcell S, Wray N, Stone J, Visscher P, O’Donovan M, Sullivan P, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748–52.
Euesden J, Lewis CM, O’Reilly PF. PRSice: Polygenic Risk Score software. Bioinformatics 2015;31:1466–8.
van Donkelaar MMJ, Hoogman M, Shumskaya E, Buitelaar JK, Bralten J, Franke B Monoamine and neuroendocrine gene-sets associate with frustration-based aggression in a gender-specific manner. Eur Neuropsychopharmacol. 2020;30:75–86.
Naaijen J, Bralten J, Poelmans G, Glennon JC, Franke B, Buitelaar JK, et al. Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism. Transl Psychiatry 2017;7:e999–7.
Blair RJ. The neurobiology of psychopathic traits in youths. Nat Rev Neurosci. 2013;14:786–99.
Byrd AL, Manuck SB. MAOA, childhood maltreatment, and antisocial behavior: Meta-analysis of a gene-environment interaction. Biol Psychiatry 2014;75:9–17.
Ruisch IH, Dietrich A, Glennon JC, Buitelaar JK, Hoekstra PJ. Maternal substance use during pregnancy and offspring conduct problems: a meta-analysis. Neurosci Biobehav Rev. 2018;84:325–36.
Afifi TO, McMillan KA, Asmundson GJG, Pietrzak RH, Sareen J. An examination of the relation between conduct disorder, childhood and adulthood traumatic events, and posttraumatic stress disorder in a nationally representative sample. J Psychiatr Res 2011;45:1564–72.
Holz NE, Zohsel K, Laucht M, Banaschewski T, Hohmann S, Brandeis D. Gene x environment interactions in conduct disorder: implications for future treatments. Neurosci Biobehav Rev. 2018;91:239–58.
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461:747–53.
Dick DM, Agrawal A, Keller MC, Adkins A, Aliev F, Monroe S, et al. Candidate gene–environment interaction research. Perspect Psychol Sci. 2015;10:37–59.
Vassos E, Collier DA, Fazel S. Systematic meta-analyses and field synopsis of genetic association studies of violence and aggression. Mol Psychiatry 2014;19:471–7.
von Rhein D, Mennes M, van Ewijk H, Groenman AP, Zwiers MP, Oosterlaan J, et al. The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives. Eur Child Adolesc Psychiatry. 2015;24:265–81.
Essau CA, Sasagawa S, Frick PJ. Callous-unemotional traits in a community sample of adolescents. Assessment 2006;13:454–69.
Viding E, Hanscombe KB, Curtis CJC, Davis OSP, Meaburn EL, Plomin R. In search of genes associated with risk for psychopathic tendencies in children: a two-stage genome-wide association study of pooled DNA. J Child Psychol Psychiatry. 2010;51:780–8.
Viding E, Price TS, Jaffee SR, Trzaskowski M, Davis OSP, Meaburn EL, et al. Genetics of callous-unemotional behavior in children. PLoS ONE 2013;8:e65789.
Logue MW, Amstadter AB, Baker DG, Duncan L, Koenen KC, Liberzon I, et al. The psychiatric genomics consortium posttraumatic stress disorder workgroup: posttraumatic stress disorder enters the age of large-scale genomic collaboration. Neuropsychopharmacology 2015;40:2287–97.
Lam M, Awasthi S, Watson HJ, Goldstein J, Panagiotaropoulou G, Trubetskoy V, et al. RICOPILI: Rapid Imputation for COnsortias PIpeLIne. Bioinformatics. 2019;(August):1–4.
Reijneveld SA, Bosch NM, Bakker MP, Verhulst FC, Ormel J, Oldehinkel AJ. Timing matters: Long term effects of adversities from prenatal period up to adolescence on adolescents’ cortisol stress response. The TRAILS study. Psychoneuroendocrinology 2012;37:1439–47.
Keller M. Gene-by-environment interaction studies have not properly controlled for potential confounders: The problem and the (simple) solution. Biol Psychiatry 2014;75:18–24.
Auton A, Abecasis GR, Altshuler DM, Durbin RM, Bentley DR, Chakravarti A, et al. A global reference for human genetic variation. Nature 2015;526:68–74.
Choi SW, O’Reilly PF. PRSice-2: Polygenic Risk Score software for biobank-scale data. Gigascience 2019;8:1–6.
Choi SW, Mak TSH, O’Reilly PF. A guide to performing Polygenic Risk Score analyses. bioRxiv 2018.
Ruisch IH, Dietrich A, Glennon JC, Buitelaar JK, Hoekstra PJ. Interplay between genome-wide implicated genetic variants and environmental factors related to childhood antisocial behavior in the UK ALSPAC cohort. Eur Arch Psychiatry Clin Neurosci. 2019;269:741–52.
Zhang Y, Wu C, Chang H, Yan Q, Wu L, Yuan S, et al. Genetic variants in oxytocin receptor gene (OXTR) and childhood physical abuse collaborate to modify the risk of aggression in chinese adolescents. J Affect Disord. 2018;229:105–10.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.
Rice F, Harold GT, Boivin J, van den B, Hay DF, Thapar A. The links between prenatal stress and offspring development and psychopathology: disentangling environmental and inherited influences. Psychol Med 2010;40:335–45.
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2018.
Bates D, Maechler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67:1–48.
Zhang Z, Ersoz E, Lai C, Todhunter RJ, Tiwari HK, Gore MA, et al. Mixed linear model approach adapted for genome-wide association studies. Nat Genet 2010;42:355–60.
Price AL, Zaitlen NA, Reich D, Patterson N. New approaches to population stratification in genome-wide association studies. Nat Rev Genet. 2010;11:459–63.
Patterson N, Price AL, Reich D. Population structure and eigenanalysis. PLoS Genet 2006;2:e190.
Kennedy AE, Ozbek U, Dorak MT. What has GWAS done for HLA and disease associations? Int J Immunogenet. 2017;44:195–211.
van Donkelaar MMJ, Hoogman M, Pappa I, Tiemeier H, Buitelaar JK, Franke B, et al. Pleiotropic contribution of MECOM and AVPR1A to aggression and subcortical brain volumes. Front Behav Neurosci. 2018;12:61.
The Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol Autism 2017;8:21.
Bosia M, Pigoni A, Zagato L, Merlino L, Casamassima N, Lorenzi C, et al. ADDing a piece to the puzzle of cognition in schizophrenia. Eur J Med Genet. 2016;59:26–31.
Woolfrey KM, Srivastava DP, Photowala H, Yamashita M, Barbolina MV, Cahill ME, et al. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci 2009;12:1275–84.
Fukumoto K, Tamada K, Toya T, Nishino T, Yanagawa Y, Takumi T. Identification of genes regulating GABAergic interneuron maturation. Neurosci Res 2017;134:18–29.
Purkayastha P, Malapati A, Yogeeswari P, Sriram D. A review on GABA/glutamate pathway for therapeutic intervention of ASD and ADHD. Curr Med Chem. 2015;22:1850–9.
Ripke S, Neale BM, Corvin A, Walters JTR, Farh KH, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421–7.
Cima M, Raine A, Meesters C, Popma A. Validation of the Dutch Reactive Proactive Questionnaire (RPQ): differential correlates of reactive and proactive aggression from childhood to adulthood. Aggress Behav 2013;39:99–113.
Ueno K, Ackermann K, Freitag CM, Schwenck C. Assessing Callous–Unemotional Traits in 6- to 18-Year-Olds: Reliability, Validity, Factor Structure, and Norms of the German Version of the Inventory of Callous–Unemotional Traits. Assessment. 2019; In press.
Kohannim O, Hibar DP, Stein JL, Jahansha N, Hua X, Rajagopalan P, et al. Discovery and replication of gene influences on brain structure using LASSO regression. Front Neurosci 2012;6:115.
Kim E, Lee SH, Lee KS, Cheong HK, Namkoong K, Hong CH, et al. AMPK γ2 subunit gene PRKAG2 polymorphism associated with cognitive impairment as well as diabetes in old age. Psychoneuroendocrinology 2012;37:358–65.
McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, et al. Risperidone in children with autism and serious behavioral problems. N. Engl J Med. 2002;347:314–21.
Cohn MD, Veltman DJ, Pape LE, Van Lith K, Vermeiren RRJM, Van Den Brink W, et al. Incentive processing in persistent disruptive behavior and psychopathic traits: A functional magnetic resonance imaging study in adolescents. Biol Psychiatry 2015;78:615–24.
Murray L, Shaw DS, Forbes EE, Hyde LW. Reward-related neural correlates of antisocial behavior and callous–unemotional traits in young men. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:346–54.
Wright N, Hill J, Pickles A, Sharp H. Callous-unemotional traits, low cortisol reactivity and physical aggression in children: findings from the Wirral Child Health and Development Study. Transl Psychiatry 2019;9:79.
Popma A, Vermeiren R, Geluk CAML, Rinne T, van den Brink W, Knol DL, et al. Cortisol moderates the relationship between testosterone and aggression in delinquent male adolescents. Biol Psychiatry 2007;61:405–11.
Acknowledgements
We are very grateful to all families who participated in the NeuroIMAGE-study, and the whole NeuroIMAGE-team, including interviewers, technicians, scientists, clinicians, volunteers, and managers of all involved organizations and facilities, for recruitment and collection, and preprocessing of the data used in this study. We are very grateful to the Donders Institute for Brain, Cognition and Behavior of the Radboud University Nijmegen for granting us access to the high-performance computing environment required to conduct this study.
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I.H.R., A.D., and P.J.H. designed the study. I.H.R. wrote a manuscript draft and conducted the statistical analyses. M.K. assisted with the data analysis and interpretation of results. A.D., M.K., S.V.F., J.O., J.K.B., and P.J.H. provided both general feedback and discussed specific methodological, clinical, or theoretical issues related to the study. All authors discussed the results and implications as well as contributed and approved the final version of the manuscript.
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Ruisch, I.H., Dietrich, A., Klein, M. et al. Aggression based genome-wide, glutamatergic, dopaminergic and neuroendocrine polygenic risk scores predict callous-unemotional traits. Neuropsychopharmacol. 45, 761–769 (2020). https://doi.org/10.1038/s41386-020-0608-0
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DOI: https://doi.org/10.1038/s41386-020-0608-0
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