A common allele in the oxytocin receptor gene ( OXTR ) impacts prosocial temperament and human hypothalamic-limbic structure and function

Abstract

The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance.imaging genetics | neuroimaging | social behavior | prosocial neuropeptides | autism

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

“…Notably, the two SNPs on OXTR (rs2254298, rs53576) have been associated with individual differences in intermediate mechanisms (e.g., affiliation, stress regulation, and empathy) underlying the risk for psychopathological phenotypes—especially those with social dysfunction features (e.g., 61). Although there is no prior evidence showing that, in particular, allelic variation (rs2254298) may moderate the association of stress with PEs, several studies have linked this polymorphism with an increased risk for psychopathological outcomes (e.g., 62) and with alterations in important brain areas involved in stress reactivity and emotional responses, such as the hypothalamus and amygdala (e.g., 63). Interestingly, one study revealed that A carriers of rs225498 showed higher PANSS general symptom scores than GG individuals in a group of persons with schizophrenia, whereas no differences were found within a healthy control group 64.…”

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Nevertheless, a finding that showed higher amygdala reactivity after presentation of emotional faces in homozygous G allele carriers of the OXTR rs53576 SNP compared to A allele carriers (Tost et al, 2010) could be directly replicated in an independent sample (Dannlowski et al, 2015), showing the merit of combining functional imaging and genetic techniques. With regard to the scope of the present work, i.e.…”

Helping hands, healthy body? Oxytocin receptor gene and prosocial behavior interact to buffer the association between stress and physical health

“…Within the OXTR gene, the single nucleotide polymorphism (SNP) rs53576 has been shown to predict both stress-buffering and prosocial behavior, with the "GG" genotype, in particular, appearing to indicate greater inclination for engaging in beneficial psychological and social behaviors associated with oxytocin (Bakermans-Kranenburg and van Ijzendoorn, 2008;Rodrigues et al, 2009;Tost et al, 2010). Moreover, although the exact role of rs53576 "G" and "A" alleles remains unclear, the risk allele (A) has been associated with risk allele-load dependent decreases in hypothalamic size and amygdalar activation (Tost et al, 2010), suggesting that risk for psychosocial dysfunction increases in the presence of an "A" allele.…”

“…Moreover, although the exact role of rs53576 "G" and "A" alleles remains unclear, the risk allele (A) has been associated with risk allele-load dependent decreases in hypothalamic size and amygdalar activation (Tost et al, 2010), suggesting that risk for psychosocial dysfunction increases in the presence of an "A" allele. If this is the case, and oxytocin accounts for the stress-buffering effects of prosocial behavior on health, we would expect to see a significant interaction between prosocial behavior and the GG genotype that explains the stress-health relationship.…”

“…It was in Hardy-Weinberg equilibrium (X 2 [1] = 0.1, p > .05) with no genotype-by-sex differences (X 2 [2] = 1.32, p = .52) or genotype-by-ethnicity differences (X 2 [6] = 7.22, p = .30). We followed the same grouping strategy used in prior studies addressing genotype-related psychological and social phenotypes-GG respondents were compared to individuals carrying a high risk A allele (GG = 1, AA/AG = 0) (e.g., Poulin et al, 2012;Rodrigues et al, 2009;Tost et al, 2010). This approach maintains consistency with prior studies and ensures sufficient statistical power to detect differences related to the high risk A allele.…”