Using polygenic scores to assess liability to antisocial behavior

To date, several genome-wide association studies (GWAS) of antisocial behavior (ASB) have been conducted in Europeans, which promoted research aimed at evaluating liability to ASB-related phenotypes in independent samples. Such studies implemented a polygenic score (PGS) approach, which represents a composite score considering a number of “risky” alleles. Since no GWAS of ASB has been conducted in Russians, the present study aimed to perform a replication study of liability to severe criminal behavior (homicide) in individuals from Russia using PGS. Moreover, we sought to obtain the best model considering PGS and potential social factors as predictors. Genotyping of the “top” ten SNPs previously identified in GWAS meta-analysis of ASB (CADM2, REV3L, FOXP1, FOXP2, BDNF, FURIN, XKR6, TMEM18, SORCS3, and ZIC4 genes) was conducted via real-time PCR in 227 homicide offenders and 254 healthy donors from the Volga-Ural region of Russia. Multiple regression models included “weighted” and “unweighted” PGS and potential social factors as predictors. The best regression model of liability to severe ASB was based on genetic effects of examined SNPs and social predictors, including traumatic brain injury, severe chronic disease, and tobacco smoking, which was more pronounced among subjects with a family history of mental illness (p = 2 × 10^–13). PGS alone explained a small proportion of variance in liability to ASB (1.1–1.5 %), while the inclusion of social parameters increased variance explained (16.2–21.2 %). Revealed findings evidence a higher impact of social factors than a composite effect of selected “top” SNPs in predicting liability to ASB in the examined cohort. A higher probability of ASB was linked to comorbid substance abuse, traumatic brain injury, and family history of mental illness, which may also represent a result of a “risky” genetic profile.

1. Acheson A., Vincent A.S., Cohoon A.J., Lovallo W.R. Defining the phenotype of young adults with family histories of alcohol and other substance use disorders: studies from the family health patterns project. Addict Behav. 2018;77:247-254. doi 10.1016/j.addbeh. 2017.10.014

2. Acland E.L., Pocuca N., Paquin S., Boivin M., Ouellet-Morin I., And­ lauer T.F.M., Gouin J.P., Côté S.M., Tremblay R.E., Geoffroy M., Castellanos-Ryan N. Polygenic risk and hostile environments: links to stable and dynamic antisocial behaviors across adolescence. Dev Psychopathol. 2025;37(1):464-476. doi 10.1017/S095457942400004X

3. Antón-Galindo E., Cabana-Domínguez J., Torrico B., Corominas R., Cormand B., Fernàndez-Castillo N. The pleiotropic contribution of genes in dopaminergic and serotonergic pathways to addiction and related behavioral traits. Front Psychiatry. 2023;14:1293663. doi 10.3389/fpsyt.2023.1293663

4. Barnes J.C., Liu H., Motz R.T., Tanksley P.T., Kail R., Beckley A.L., Belsky D.W., Domingue B.W., Moffitt T.E., Pratt T.C., Wertz J. The propensity for aggressive behavior and lifetime incarceration risk: a test for gene-environment interaction (G × E) using whole-genome data. Aggres Violent Behav. 2019;49:101307.doi 10.1016/j.avb. 2019.07.002

5. Baron R.A., Richardson D.R. Human Aggression. New York: Plenum Press, 2004 Borinskaya S.A., Rubanovich A.V., Larin A.K., Kazantseva A.V., Da­ vydova Y.D., Genetozov E.V., Khusnitdinova E.K., Yankovsky N.K. Epigenome-wide association study of CpG methylation in aggressive behavior. Russ J Genet. 2021;57(12):1454-1460. doi 10.1134/S1022795421120048

6. Brislin S.J., Salvatore J.E., Meyers J.M., Kamarajan C., Plawecki M.H., Edenberg H.J., Kuperman S., … Kramer J.R., Chan G., Porjesz B.; COGA Collaborators; Dick D.M. Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood. Psychol Med. 2024;54(2):267-277. doi 10.1017/S0033291723001174

7. Burt S.A. The genetic, environmental, and cultural forces influencing youth antisocial behavior are tightly intertwined. Annu Rev Clin Psychol. 2022;18:155-178. doi 10.1146/annurev-clinpsy-072220-015507

8. Davydova Y., Kazantseva A., Enikeeva R., Mustafin R., Malykh S., Lobaskova M., Valinurov R., Akhmerova I., Khusnutdinova E. The involvement of hypothalamic-pituitary-adrenal and monoaminergic systems genes in developing aggressive behavior. Eur Neuropsychopharmacol. 2020a;31(S1):S16-S17. doi 10.1016/j.euroneuro.2019. 12.023

9. Davydova Y.D., Kazantseva A.V., Enikeeva R.F., Mustafin R.N., Lobaskova M.M., Malykh S.B., Gilyazova I.R., Khusnutdinova E.K. The role of oxytocin receptor (OXTR) gene polymorphisms in the development of aggressive behavior in healthy individuals. Russ J Genet. 2020b;56(9):1129-1138. doi 10.1134/S1022795420090057

10. Deng W.Q., Belisario K., Gray J.C., Levitt E.E., Mohammadi-Shemi­ rani P., Singh D., Pare G., MacKillop J. Leveraging related health phenotypes for polygenic prediction of impulsive choice, impulsive action, and impulsive personality traits in 1534 European ancestry community adults. Genes Brain Behav. 2023;22(3):e12848. doi 10.1111/gbb.12848

11. Dotterer H.L., Hyde L.W., Swartz J.R., Hariri A.R., Williamson D.E. Amygdala reactivity predicts adolescent antisocial behavior but not callous-unemotional traits. Dev Cogn Neurosci. 2017;24:84-92. doi 10.1016/j.dcn.2017.02.008

12. Fritz M., Soravia S.M., Dudeck M., Malli L., Fakhoury M. Neurobio­ logy of aggression-review of recent findings and relationship with alcohol and trauma. Biology (Basel). 2023;12(3):469. doi 10.3390/biology12030469

13. Gould T.J. Epigenetic and long-term effects of nicotine on biology, behavior, and health. Pharmacol Res. 2023;192:106741. doi 10.1016/j.phrs.2023.106741

14. Guskiewicz K.M., McCrea M., Marshall S.W., Cantu R.C., Randolph C., Barr W., Onate J.A., Kelly J.P. Cumulative effects associated with recurrent concussion in collegiate football players: the NCAA Concussion Study. JAMA. 2003;290(19):2549-2555. doi 10.1001/jama.290.19.2549

15. Han M.J., Kim S.T., Park C.I., Hwang S.S., Kim H.W., Kang J.I., Kim S.J. Serial mediating effects of childhood trauma and conduct behaviors on the impact of family history among patients with alcohol use disorder. Sci Rep. 2024;14(1):7196. doi 10.1038/s41598-024-57861-x

16. Heilbronner U., Papiol S., Budde M., Andlauer T.F.M., Strohmaier J., Streit F., Frank J., … Stürmer T., Müller-Myhsok B., Nöthen M.M., Rietschel M., Schulze T.G. “The Heidelberg Five” personality dimensions: genome-wide associations, polygenic risk for neuroticism, and psychopathology 20years after assessment. Am J Med Genet B Neuropsychiatr Genet. 2021;186(2):77-89. doi 10.1002/ajmg.b.32837

17. Iacono W.G. Endophenotypes in psychiatric disease: prospects and challenges. Genome Med. 2018;10(1):11. doi 10.1186/s13073-018-0526-5

18. Ip H.F., Van der Laan C.M., Krapohl E.M.L., Brikell I., SánchezMora C., Nolte I.M., St Pourcain B., … Lundström S., Plomin R., Bartels M., Nivard M.G., Boomsma D.I. Genetic association study of childhood aggression across raters, instruments, and age. Transl Psychiatry. 2021;11(1):413. doi 10.1038/s41398-021-01480-x

19. Karlsson Linnér R., Biroli P., Kong E., Meddens S.F.W., Wedow R., Fontana M.A., Lebreton M., … Lee J.J., Cesarini D., Benjamin D.J., Koellinger P.D., Beauchamp J.P. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nat Genet. 2019;51(2):245-257. doi 10.1038/s41588-018-0309-3

20. Karlsson Linnér R., Mallard T.T., Barr P.B., Sanchez-Roige S., Mado­ le J.W., Driver M.N., Poore H.E., … Waldman I.D., Palmer A.A., Harden K.P., Koellinger P.D., Dick D.M. Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction. Nat Neurosci. 2021;24(10):1367- 1376. doi 10.1038/s41593-021-00908-3

21. Kazantseva A.V., Kutlumbetova Yu.Yu., Malykh S.B., Lobaskova M.M., Khusnutdinova E.K. Arginine-vasopressin receptor gene (AVPR1A, AVPR1B) polymorphisms and their relation to personality traits. Russ J Genet. 2014;50(3):298-307. doi 10.1134/S10227954140 30041

22. Kazantseva A.V., Malykh S.B., Khusnutdinova E.K. Molecular-genetic studies of personality: from gene candidate analyses to genome-wide association studies. In: Malykh S.B., Kovas Y.V., Gaysina D.A. (Eds) Genomics of Behavior: Children Development and Education. Tomsk: Tomsk State University, 2016;178-209 (in Russian)

23. Kazantseva A.V., Davydova Y.D., Enikeeva R.F., Valinurov R.G., Gareeva A.E., Khusnutdinova N.N., Khusnutdinova E.K. The association study of polymorphic variants of hypothalamic-pituitary- adrenal system genes (AVPR1B, OXTR) and aggressive behavior manifestation: a focus on social environment. Res Results Biomed. 2021;7(3):232-244. doi 10.18413/2658-6533-2021-7-3-0-3

24. Kazantseva A., Davydova Y., Enikeeva R., Mustafin R.N., Malykh S., Lobaskova M., Kanapin A., Prokopenko I., Khusnutdinova E. A combined effect of polygenic scores and environmental factors on individual differences in depression level. Genes. 2023a;14(7):1355. doi 10.3390/genes14071355

25. Kazantseva A.V., Davydova Y.D., Enikeeva R.F., Yakovleva D.V., Mustafin R.N., Lobaskova M.M., Malykh S.B., Khusnutdinova E.K. Individual variance in human aggression: a combined effect of polygenic score and social/lifestyle factors. Russ J Genet. 2023b;59(S2): S227-S236. doi 10.1134/s1022795423140065

26. Li W., Zhou H., Thygesen J.H., Heydtmann M., Smith I., Degenhardt F., Nöthen M., Morgan M.Y., Kranzler H.R., Gelernter J., Bass N., McQuillin A. Genome-wide association study of antisocial personality disorder diagnostic criteria provides evidence for shared risk factors across disorders. Psychiatr Genet. 2023;33(6):233-242. doi 10.1097/YPG.0000000000000352

27. Manchia M., Fanos V. Targeting aggression in severe mental illness: the predictive role of genetic, epigenetic, and metabolomic markers. Prog Neuropsychopharmacol Biol Psychiatry. 2017;77:32-41. doi 10.1016/j.pnpbp.2017.03.024

28. Mbatchou J., Barnard L., Backman J., Marcketta A., Kosmicki J.A., Ziyatdinov A., Benner C., … Baras A., Reid J., Abecasis G., Maxwell E., Marchini J. Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet. 2021;53(7): 1097-1103. doi 10.1038/s41588-021-00870-7

29. McAdams T.A., Gregory A.M., Eley T.C. Genes of experience: explaining the heritability of putative environmental variables through their association with behavioural and emotional traits. Behav Genet. 2013;43(4):314-328. doi 10.1007/s10519-013-9591-0

30. Musci R.J., Bettencourt A.F., Sisto D., Maher B., Masyn K., Ialongo N.S. Violence exposure in an urban city: a G×E interaction with aggressive and impulsive behaviors. J Child Psychol Psychiatry. 2019;60(1):72-81. doi 10.1111/jcpp.12966

31. Odintsova V.V., Hagenbeek F.A., van der Laan C.M., van de Weijer S., Boomsma D.I. Genetics and epigenetics of human aggression. Handb Clin Neurol. 2023;197:13-44. doi 10.1016/B978-0-12-821375-9.00005-0

32. Pappa I., St Pourcain B., Benke K., Cavadino A., Hakulinen C., Nivard M.G., Nolte I.M., … Middeldorp C.M., Oldehinkel A.J., Pennell C.E., Boomsma D.I., Tiemeier H. A genome-wide approach to children’s aggressive behavior: the EAGLE consortium. Am J Med Genet B Neuropsychiatr Genet. 2016;171(5):562-572. doi 10.1002/ajmg.b.32333

33. Pezzoli P., McCrory E.J., Viding E. Shedding light on antisocial behavior through genetically informed research. Annu Rev Psychol. 2025;76(1):797-819. doi 10.1146/annurev-psych-021524-043650

34. Ryan N.P., Catroppa C., Hughes N., Painter F.L., Hearps S., Beauchamp M.H., Anderson V.A. Executive function mediates the prospective association between neurostructural differences within the central executive network and anti-social behavior after childhood traumatic brain injury. J Child Psychol Psychiatry. 2021;62(9): 1150-1161. doi 10.1111/jcpp.13385

35. Schwartz J.A., Solomon S.J., Valgardson B.A. Socialization, selection, or both? The role of gene-environment interplay in the association between exposure to antisocial peers and delinquency. J Quant Criminol. 2019;35:1-26. doi 10.1007/s10940-017-9368-3

36. Tesli N., Jaholkowski P., Haukvik U.K., Jangmo A., Haram M., Rokicki J., Friestad C., Tielbeek J.J., Næss Ø., Skardhamar T., Gustavson K., Ask H., Fazel S., Tesli M., Andreassen O.A. Conduct disorder – a comprehensive exploration of comorbidity patterns, genetic and environmental risk factors. Psychiatry Res. 2024;331:115628. doi 10.1016/j.psychres.2023.115628

37. Theadom A., Jones K., Starkey N., Barker-Collo S., Ameratunga S., Faulkner J., Ao B.T., Feigin V. Symptoms and engagement in antisocial behavior 10 years after mild traumatic brain injury within a community civilian sample: a prospective cohort study with age-sex matched control group. Arch Phys Med Rehabil. 2024;105(2):295- 302. doi 10.1016/j.apmr.2023.07.016

38. Tielbeek J.J., Johansson A., Polderman T.J.C., Rautiainen M.R., Jansen P., Taylor M., Tong X., … Faraone S.V., Popma A., Medland S.E., Posthuma D.; Broad Antisocial Behavior Consortium collaborators. Genome-wide association studies of a broad spectrum of antisocial behavior. JAMA Psychiatry. 2017;74(12):1242-1250. doi 10.1001/jamapsychiatry.2017.3069

39. Tielbeek J.J., Uffelmann E., Williams B.S., Colodro-Conde L., Gagnon É., Mallard T.T., Levitt B.E., … Fisher S.E., Moffitt T.E., Caspi A., Polderman T.J.C., Posthuma D. Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis. Mol Psychiatry. 2022;27(11):4453- 4463. doi 10.1038/s41380-022-01793-3

40. van Goozen S.H.M., Langley K., Hobson C.W. Childhood antisocial behavior: a neurodevelopmental problem. Annu Rev Psychol. 2022; 73:353-377. doi 10.1146/annurev-psych-052621-045243

41. Wang S., Dan Y.L., Yang Y., Tian Y. The shared genetic etiology of antisocial behavior and psychiatric disorders: insights from pleiotropy and causality analysis. J Affect Disord. 2024;365:534-541. doi 10.1016/j.jad.2024.08.149

42. Watanabe K., Stringer S., Frei O., Umićević Mirkov M., de Leeuw C., Polderman T.J.C., van der Sluis S., Andreassen O.A., Neale B.M., Posthuma D. A global overview of pleiotropy and genetic architecture in complex traits. Nat Genet. 2019;51(9):1339-1348. doi 10.1038/s41588-019-0481-0

43. Weltens I., Bak M., Verhagen S., Vandenberk E., Domen P., van Amelsvoort T., Drukker M. Aggression on the psychiatric ward: prevalence and risk factors. A systematic review of the literature. PLoS One. 2021;16(10):e0258346. doi 10.1371/journal.pone.0258346