Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation and child autistic traits: The moderating role of OXTR rs53576 genotype

Lay Abstract: The gene encoding the oxytocin receptor (OXTR), localized on chromosome 3p25, is considered a promising candidate for explaining genetic vulnerability to autistic traits. Although several lines of evidence implicate OXTR SNP rs53576 (G/A) variation in social behavior, findings have been inconsistent, possibly because DNA methylation after stress exposure was eliminated from consideration. This study investigated the main and interactive effects of OXTR rs53576 genotype, stress exposure, and OXTR methylation on child autistic traits. Prenatal maternal stress exposure, but not OXTR rs53576 genotype and OXTR methylation, showed a main effect on child autistic traits. For child autistic traits in general and social communication problems in particular, we observed a significant OXTR rs53576 genotype by OXTR methylation interaction. More specifically, OXTR methylation levels were positively associated with social problems for OXTR rs53576 G-allele homozygous children but not for A-allele carriers. These results highlight the importance of incorporating epi-allelic information and support the role of OXTR methylation in child autistic traits. Scientific Abstract: Findings of studies investigating OXTR SNP rs53576 (G-A) variation in social behavior have been inconsistent, possibly because DNA methylation after stress exposure was eliminated from consideration. Our goal was to examine OXTR rs53576 allele-specific sensitivity for neonatal OXTR DNA methylation in relation to (1) a prenatal maternal stress composite, and (2) child autistic traits. Prospective data from fetal life to age 6 years were collected in a total of 743 children participating in the Generation R Study. Prenatal maternal stress exposure was uniquely associated with child autistic traits but was unrelated to OXTR methylation across both OXTR rs53576 G-allele homozygous children and A-allele carriers. For child autistic traits in general and social communication problems in particular, we observed a significant OXTR rs53576 genotype by OXTR methylation interaction in the absence of main effects, suggesting that opposing effects cancelled each other out. Indeed, OXTR methylation levels were positively associated with social problems for OXTR rs53576 G-allele homozygous children but not for A-allele carriers. These results highlight the importance of incorporating epi-allelic information and support the role of OXTR methylation in child autistic traits.

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