Situating the oxytocin receptor gene polymorphisms in the context of structural and connectome-level substrates and association with endogenous oxytocin

Genetic variants in the oxytocin receptor (OXTR) have been linked to individual differences in social behavior, while aberrant oxytocin regulation is associated with increased susceptibility to neuropsychiatric disorders. Recent magnetic resonance imaging (MRI) studies have demonstrated altered brain morphology and connectivity in response to OXTR single nucleotide polymorphisms (SNP) of GG homozygous compared to targeted allele carriers, such as T or A. However, the sex-specific differences in the structural and connectome-level substrates of OXTR genetic variants and their relationship with endogenous oxytocin remain poorly understood. Therefore, we aimed to decompose structural MRI and functional/structural connectivity to identify sex-specific differences among young adults through OXTR SNPs (rs53576, rs1042778, and rs2254298). High-resolution 3D T1-weighted, resting-state functional, and diffusion tensor images were acquired by sixty-one participants who provided blood samples for quantification of endogenous oxytocin concentrations and use for genotyping, followed by grouping with respect to homozygous and targeted allele carriers. We found that men had greater cortical surface area and sub(cortical) gray matter volume in different homozygous and targeted allele carriers. Resting-state functional and structural connectivity (rsFC and SC, respectively) were allocated differently, primarily in temporal and subcortical brain regions. There were also significant sex-specific differences in mean correlations between endogenous oxytocin and SC, whereas rsFC delineated more significant correlations on the node level. Our results provide valuable insights into sex-specific differences in the structural and connectome-level substrates of OXTR SNPs, contributing to understanding the role of oxytocin in socio-emotional processing and highlighting sex-specific differences in genetic and neural mechanisms underlying social behavior.