Association between a polymorphism of the vasopressin 1B receptor gene and aggression in children Daniella Luppino a , Caroline Moul a , David J. Hawes c , John Brennan b and Mark R. Dadds a Objectives The involvement of arginine–vasopressin (AVP) in animal and human aggression has been well established in the literature. Recent research has shown an association between the minor allele (C) of single-nucleotide polymorphism rs35369693 located on the AVP 1B receptor gene and childhood aggression. Materials and methods The present study sought to replicate the association between rs35369693 and aggression using a sample of clinically referred children (N = 141) with behavioural problems. Results Analyses confirmed a significant relationship between the minor C allele on rs35369693 and teacher- rated reactive aggression. Although males had significantly greater aggression than females on three of the four measures, sex was not shown to moderate the effect of the C allele on any of the aggression measures. Conclusion These findings reinforce the results from previous research and also suggest that the associations of the AVP 1B receptor may be specific to reactive, emotional rather than proactive or callous types of aggression. Psychiatr Genet 24:185–190 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Psychiatric Genetics 2014, 24:185–190 Keywords: AVP 1B, child aggression, genetics, reactive aggression, rs35369693, vasopressin a School of Psychology, b School of Psychiatry, The University of New South Wales and c School of Psychology, The University of Sydney, Sydney, New South Wales, Australia Correspondence to Mark R. Dadds, PhD, School of Psychology, The University of New South Wales, Sydney, NSW 2052, Australia Tel: + 61 2 9385 3538; fax: + 61 2 9385 3641; e-mail: m.dadds@unsw.edu.au Received 24 July 2013 Revised 27 January 2014 Accepted 10 April 2014 Introduction Decades of research have identified environmental and biological factors influencing the development of aggression in both human and animal models [see Anderson and Bushman (2002) for a review]. More recently, accumulating evidence has emerged suggesting genetic contributions to aggression (Rujescu et al., 2003; McDermott et al., 2009). In particular, arginine–vasopressin (AVP) has been implicated in the development of aggres- sion in both human and animal models (Heinrichs and Domes, 2008; Heinrichs et al., 2009). A recent study by Zai et al. (2012) examined the relationship between the AVP system and childhood aggression by testing 11 single- nucleotide polymorphisms (SNP) on the AVP 1A and 1B receptor genes. They identified a significant association between allele frequencies of SNP rs35369693 located on the AVP 1B gene and aggressive versus case–control group membership. Specifically, the minor allele (C) on rs35369693 was more frequent in a clinical child sample [defined by ≥ 90th percentile on aggression scales on the Child Behavior Checklist and Teacher’s Report Form (Achenbach and Rescorla, 2001) and at least a 2-year history of aggressive behaviour] compared with adult controls mat- ched for sex and ethnicity. The rs35369693 SNP is an exonic, nonsynonymous missense polymorphism that codes for a variation at amino acid 65 on the AVP 1B gene. The normalized probability of 0.02 generated by the SIFT tool predicts that mutations of the rs35369693 SNP are damaging [see Sorting Intolerant From Tolerant tool (http://sift.bii.a-star. edu.sg)]. Alongside the findings of Zai and colleagues, these features suggest that the vasopressin system, and this SNP in particular, may be functionally significant in the development of human aggression and invoke several questions in need of clarification. First, independent replication of the findings is vital, particularly in genetic research (Ioannidis et al., 2001). Second, operationalizing ‘aggression’ as a categorical variable represented by an aggressive clinical child sam- ple compared with adult ‘nonclinical’ controls makes it difficult to control for other potential confounds that commonly differ between clinically referred cases and controls. Third, there are well-established sex differences in the level, expression and function of aggression (Eagly and Steffen, 1986). The vasopressin system may be a potential mechanism accounting for these differences as previous research has shown the effects of AVP to be sex specific (Thompson et al., 2006). This has also been shown with the AVP 1A receptor in animal models, where the effect of AVP on aggression has been shown to be sexually dimorphic (Gutzler et al., 2010). The rs35369693 SNP in particular has also been shown to be associated with childhood-onset depressive and bipolar disorders specifically in females (Dempster et al., 2007), providing further justification for an exploration of other sex-specific effects. Finally, although an association Original article 185 0955-8829 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YPG.0000000000000036 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.