Multiple Oxytocin Receptor Gene (OXTR) Loci Coalesce to Impact Structural Connectivity in Children with Autism

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­­Background: Recent neuroimaging-genetics research suggests that common single nucleotide polymorphisms (SNPs) associated with increased risk for Autism Spectrum Disorder (ASD) diagnosis may predispose to ASD through their effects on brain connectivity (e.g., Rudie, 2012). Given that social deficits are a core feature of ASD, here we examined a gene linked to increased risk for ASD diagnosis, as well as social and affiliative behavior across species: the oxytocin receptor gene (OXTR). Genetics research has identified an association between increased risk for ASD and multiple OXTR SNPs (e.g., Wu, 2005; Jacob, 2007). Findings of multiple risk loci on the OXTR gene in ASD support a “multiple-hits” model of autism etiology in which individuals who carry greater numbers of risk alleles are at increased likelihood for presenting more atypical neural endophenotypes (Huguet, 2013).

Objectives: Here, we investigated how the presence of risk alleles across multiple OXTR SNP loci may coalesce to produce an additive effect on structural connectivity in typically developing children (TD) and children with ASD. We explored two models: 1. How multiple ASD-associated OXTR SNPs impact whole brain structural connectivity. 2. How multiple social behavior-associated OXTR SNPs impact whole brain structural connectivity.

Methods: DNA was extracted from saliva samples and genotyped for six ASD-associated OXTR SNPs (rs53576, rs1042778, rs2254298, rs237884, rs237895, rs7632287) and two social behavior-associated SNPs (rs237887, rs2268491). Sixty-two children (31ASD, 31TD) underwent 32-direction diffusion tensor imaging (DTI). Data was analyzed using Tract Based Spatial Statistics (Smith, 2006) to investigate voxelwise white matter (WM) fractional anisotropy (FA; a measure of fiber integrity). Total number of risk alleles across SNPs was used to create an aggregate risk score for each subject and entered as a covariate to assess whether the relationship between FA and aggregate risk score differs between the two diagnostic groups (TD and ASD).

Results: Greater numbers of ASD-associated OXTR SNPs were associated with decreased FA in the ASD group in the bilateral body of the corpus callosum, left inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left external capsule, left internal capsule, and left uncinate fasciculus (p<0.05, corrected). A significant interaction was present such that greater aggregate risk sores were associated with reduced FA in ASD participants above the effect observed in TD participants (p<0.05, uncorrected). When additional OXTR SNPs related to social behavior were added to the aggregate risk score, greater numbers of risk alleles were associated with decreased FA in the body of the corpus callosum bilaterally and left superior longitudinal fasciculus for the combined TD and ASD group (p<0.05, corrected), as well as for the TD and ASD groups separately (p<0.05, uncorrected).

Conclusions: Our results indicate that aggregate OXTR risk is associated with reduced WM fiber integrity in long-range fiber tracts connecting anterior and posterior brain regions in TD and ASD children and reduced WM integrity in tracts connecting subcortical and limbic structures (in ASD participants only). These data suggest that OXTR SNPs influence patterns of structural brain connectivity, which may be modulated by diagnostic status and vary as a function of aggregate risk status.