A key gene modulating oxytocin efficacy in autism: genome-wide discovery and verification in randomized controlled trials datasets

Previous studies suggest that oxytocin has therapeutic potential for modulating core symptoms of autism spectrum disorder (ASD), although findings have been inconsistent. The unknown mechanisms underlying oxytocin’s effects and the substantial individual variability in treatment response impede the development of effective oxytocin-based therapies. In this study, we conducted a genome-wide association study (GWAS) using data from a randomized controlled trial (RCT) that examined the effects of a single dose oxytocin on behavioral and neural correlates of ASD. We further tested the association between the SNP identified in the GWAS and clinical efficacy in an independent, larger dataset comprising participants from three additional RCTs. In these trials, males with high-functioning ASD received repeated doses of oxytocin, and treatment response was assessed using the social reciprocity domain of the Autism Diagnostic Observation Schedule (ADOS), the common primary outcome across all three studies. The GWAS identified a significant association between oxytocin-induced improvements in medial prefrontal cortex activity during a social judgment task and the single nucleotide polymorphism (SNP) rs1871303 in the ryanodine receptor 2 (RYR2) gene (β = 2.37, t = 7.82, df = 72, P = 3.47 × 10⁻⁹). The validation analysis supported the association between this RYR2 SNP and individual variability in ADOS reciprocity improvement (β = 0.194, t = 2.30, df = 135, P = 0.023), with no significant association observed for placebo response (P > 0.1). To our knowledge, this is the first GWAS to investigate the pharmacogenomics of oxytocin efficacy in ASD. These findings highlight RYR2 as a key gene influencing oxytocin response, possibly through its role in calcium channel signaling and regulation of endogenous oxytocin release.