Investigating the Downstream Influence of MET C Allele at rs1858830 on Neuroimaging Intermediate Phenotypes in Autism Spectrum Disorder

Abstract

<p>Appropriate social behaviour depends on the wiring together of relevant sensory and cognitive neural circuits during development and is impaired in Autism Spectrum Disorder (ASD). A functional variant of the <em>MET</em> gene at rs1858830 confers risk for ASD and a basic mechanistic hypothesis relating <em>MET</em> gene function to ASD has been proposed: Decreased MET protein expression during development increases the risk of ASD-relevant circuit miswiring. In the human, robust MET is localized to the posterior cingulate, inferior temporal, posterior parietal, and visual cortices, including face-processing regions. This pattern is consistent with the importance of vision in the social milieu of primates, suggesting a conserved developmental function of the MET receptor in facilitating the neural connectivity that allows for appropriate social behaviour. This study investigates the down-stream influence of the <em>MET</em> C allele at rs1858830 on morphological characteristics of brain regions involved in social processing of audiovisual information. We used an imaging-genetics approach to characterize neuroimaging intermediate phenotypes associated of the <em>MET</em> C allele in individuals with ASD (n= 14) and neurotypical controls. Audiovisual stimuli were presented in an emotion-matching task intended to engage diffuse networks of brain regions involved in cross-modal perceptual integration. We present modest evidence of an enhanced penetrance of the <em>MET </em>C risk allele in individuals with ASD, reflecting a mechanism whereby a common variant that is not disorder-causing in and of itself has a larger effect on network function in individuals with ASD compared to neurotypical individuals. Subtle differences between ASD and TD individuals were revealed when the cohort was stratified by <em>MET</em> risk genotype, demonstrating the potential power for an imaging-genetic approach to resolve phenotypic heterogeneity in ASD. Definition of neuroimaging intermediate phenotypes may prove to be a sensitive means of parsing out ASD subgroups, and could ultimately lead to the development of tailored therapeutic interventions.</p>