Genetic modulation of oxytocin sensitivity: a pharmacogenetic approach

Abstract

Intranasal administration of the neuropeptide oxytocin has been shown to influence a range of complex social cognitions and social behaviors, and it holds therapeutic potential for the treatment of mental disorders characterized by social functioning deficits such as autism, social phobia and borderline personality disorder. However, considerable variability exists in individual responses to oxytocin administration. Here, we undertook a study to investigate the role of genetic variation in sensitivity to exogenous oxytocin using a socioemotional task. In a randomized, double-blind, placebo-controlled experiment with a repeated-measures (crossover) design, we assessed the performance of 203 men on an emotion recognition task under oxytocin and placebo. We took a haplotype-based approach to investigate the association between oxytocin receptor gene variation and oxytocin sensitivity. We identified a six-marker haplotype block spanning the promoter region and intron 3 that was significantly associated with our measure of oxytocin sensitivity. Specifically, the TTCGGG haplotype comprising single-nucleotide polymorphisms rs237917-rs2268498-rs4564970-rs237897-rs2268495-rs53576 is associated with increased emotion recognition performance under oxytocin versus placebo, and the CCGAGA haplotype with the opposite pattern. These results on the genetic modulation of sensitivity to oxytocin document a significant source of individual differences with implications for personalized treatment approaches using oxytocin administration.

Figure 1

Upper panel a shows the location of the single-nucleotide polymorphisms (SNPs) along the OXTR gene. Lower panel b shows the linkage disequilibrium map of the OXTR SNPs genotyped in our sample produced by Haploview.

Figure 2

Graph shows relative oxytocin sensitivity across groups for the six-marker haplotype block rs237917–rs2268498–rs4564970–rs237897–rs2268495–rs53576. Oxytocin sensitivity was indexed in terms of emotion recognition speed under oxytocin compared with placebo. Higher values indicate faster reaction times under oxytocin.

Figure 3

Graph shows relative oxytocin sensitivity across groups for the three-marker haplotype block rs2254298–rs2268494–rs9840864. Oxytocin sensitivity was indexed in terms of emotion recognition speed under oxytocin compared with placebo. Higher values indicate faster reaction times under oxytocin.