Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder

Abstract

The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

Fig. 1.

Plasma OXT concentrations do not significantly differ by group, sex, or OXTR SNPs. Group: n = 47 autistic, n = 32 PDD-NOS, n = 52 sibling, and n = 62 neurotypical control children. Sex: n = 62 females and n = 131 males. rs2254928 genotype: n = 127 GG and n = 66 AG or AA. rs53576 genotype: n = 35 AA and n = 158 GG or AG. Box plots are presented as least-squares-mean (LSM) ± SEM and each LSM is partialed for other data in the analysis.

Fig. 2.

Plasma OXT concentrations predict (A) NEPSY theory of mind and (B) Vineland Communication Domain scores independent of group. Groups and sample sizes are detailed in Fig. 1. In A and B the intercepts (i.e., the mean phenotypic scores) differ significantly by group (P < 0.05), whereas the slopes of the lines do not. The overall regression line averaged across groups is significant. The phenotypic data corrected for other variables in the analysis is shown, and each line is plotted between the full extents of the data. Data points are presented as LSM ± SEM for each quintile of the data, ordered by OXT concentrations within each group.

Fig. 3.

Narrow-sense heritability is estimated as a function of within-family consistency. Individual values are shown for (A) plasma OXT concentrations (h² = 85.5%; n = 47 families) and (B) the NEPSY theory of mind score (h² = 55.1%; n = 37 families). To illustrate consistency of values within families, members of the same family are plotted at the same point on the x axis and joined by a vertical line.

Fig. 4.

OXTR SNPs predict social functioning independent of group. Groups and sample sizes are detailed in Fig. 1. For each genotype, the study risk allele is shown as a hatched bar. (A) Carriers with the G allele (n = 158) vs. those with the AA genotype (n = 35) of rs53576 show diminished affect recognition. (B) Carriers with the A allele (n = 66) vs. those with the GG genotype (n = 127) of rs2254928 show greater social impairments on the reverse-scored SRS. Data points are presented as LSM ± SEM, with the LSM partialed for all nondepicted variables. The asterisk represents Bonferroni-corrected post hoc comparison with P < 0.05.