Trust mean score by genotyped groups.

<div><p>Trust is an essential human trait. Although research suggests that the interplay between oxytocinergic and dopaminergic systems affects trust formation, little research has focused on epistatic (i.e., gene by gene) interaction effects of oxytocin- and dopamine-related genes on trust. Using a sample of 348 adults (114 men), we aimed to investigate the associations between genetic variants in oxytocin- and dopamine-related genes and the general, neighborhood, and institutional trust with consideration of sex differences. Three-way interaction between oxytocin-related gene genotypes, dopamine-related genotypes, and sex was found for the oxytocin receptor gene (<i>OXTR</i>)rs1042778 and the Catechol-O-Methyltransferase gene (<i>COMT</i>) rs4680 genotypes (p = 0.02) and for <i>OXTR</i> rs2254298 and the dopamine D2 receptor gene (<i>DRD2</i>) rs1800497 genotypes (p = 0.01). Further sex-stratified analyses revealed that the interaction between <i>OXTR</i> rs1042778 and <i>COMT</i> rs4680 genotypes was associated with neighborhood trust among men (p = 0.0007). Also, the interaction between <i>OXTR</i> rs2254298 and <i>DRD2</i> rs1800497 genotypes was associated with institutional trust among men (p = 0.005). Post-hoc analyses found that men with <i>OXTR</i> rs1042778 TG/TT and <i>COMT</i> rs4680 GG genotypes reported higher neighborhood trust than those with GG + AG/AA (B = 13.49, SE = 4.68, p = 0.02), TG/TT + AG/AA (B = 23.00, SE = 5.99, p = 0.001), and GG + GG (B = 18.53, SE = 5.25, p = 0.003). Similarly, men with <i>OXTR</i> rs2254298 AG/AA and <i>DRD2</i> rs1800497 CC genotypes showed higher institutional trust than those with AG/AA + TT/TC (B = 15.67, SE = 5.30, p = 0.02). We could not find any interacting associations among women. While we note that our sample size and candidate gene approach have a potential risk of chance findings, our study provides an important foundation toward further exploration of sex-specific epistatic interaction effects of oxytocin- and dopamine-related genes on trust, indicating the importance of both systems in trust formation.</p></div>