Autism-Associated Promoter Variant in MET Impacts Functional and Structural Brain Networks

Abstract

SUMMARY As genes that confer increased risk for autism spectrum disorder (ASD) are identified, a crucial next step is to determine how these risk factors impact brain structure and function and contribute to disorder heterogeneity. With three converging lines of evidence, we show that a common, functional ASD risk variant in the Met Receptor Tyrosine Kinase (MET) gene is a potent modulator of key social brain circuitry in children and adolescents with and without ASD. MET risk genotype predicted atypical fMRI activation and deactivation patterns to social stimuli (i.e., emotional faces), as well as reduced functional and structural connectivity in temporo-parietal regions known to have high MET expression, particularly within the default mode network. Notably, these effects were more pronounced in individuals with ASD. These findings highlight how genetic stratification may reduce heterogeneity and help elucidate the biological basis of complex neuropsychiatric disorders such as ASD.

Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan

“…92,[112][113][114] Furthermore, important properties of network connectivity seem to be altered in ASD; for example, the development of domain-specifi c function modules is reduced. 115,116 Although local connectivity within central hubs or rich clubs (ie, high-degree nodes that are more densely connected among themselves than nodes of a lower degree) seems to be increased, 117 the hub organisation is altered across the brain. 118 Taken together, fi ndings from functional activation and functional connectivity studies suggest that, in children with autism, widespread patterns of developmental disconnection aff ect information processing at both the local and global levels; furthermore, the specifi c patterns of connectivity abnormalities relate to the severity of the autism phenotype.…”

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics

“…The DMN has been shown to be involved in internally directed cognition, as it is deactivated during goal-directed behaviors and shows an anticorrelated relationship with the 'attentional control network' (Stevens et al, 2009). In children, adolescents, and adults with ASD, reports consistently suggest that connectivity between nodes of the DMN is diminished (Assaf et al, 2010;Cherkassky et al, 2006;Kennedy and Courchesne, 2008a, b;Monk et al, 2009;Rudie et al, 2012a;Weng et al, 2010). This is consistent with the known role of specific DMN nodes in tasks of social cognition (eg, watching social interactions; Iacoboni et al, 2004) and the observed behavioral deficits characteristic of ASD (ie, atypical TOM processing and social interactions).…”

“…To date, neuroimaging-genetics studies have taken two forms: studies of the effects of ASD-associated risk alleles on brain measures in neurotypical children, adolescents, and adults (eg, Clemm von Hohenberg et al, 2013; Dennis et al, Hedrick et al, 2012;Raznahan et al, 2012;Sauer et al, 2012;Tan et al, 2010;Voineskos et al, 2011;Whalley et al, 2011) and studies comparing the effects of ASD-associated risk alleles on children and adolescents with ASD compared with neurotypical controls (eg, Rudie et al, 2012a;. investigated the impact of the contactin-associated protein-like 2 (CNTNAP2) rs2710102, C risk allele on functional connectivity in children and adolescents with ASD.…”

“…A second study by Rudie et al (2012a) found that children and adolescents carrying the met receptor tyrosine kinase (MET) rs1858830, C risk allele had decreased functional connectivity between the PCC and MPFC and reduced WM integrity in the splenium of the corpus callosum, cortical spinal tract, and inferior longitudinal fasciculus. Interestingly, the authors also identified a significant interaction whereby the presence of one or two risk alleles in ASD children had a significantly larger impact on functional connectivity values than in neurotypical children.…”

The Promise of Multi-Omics and Clinical Data Integration to Identify and Target Personalized Healthcare Approaches in Autism Spectrum Disorders

“…In one study using sMRI (Qureshi et al, 2014), a mirror phenotype of brain volume was observed for individuals with ASD and a copy number variation within the 16p11.2 locus, such that compared to controls, deletion carriers exhibited increases and duplication carriers exhibited decreases in brain size. Other work has associated autism risk genes to structural and functional brain connectivity (e.g., CNTNAP2) (Dennis et al, 2011;Rudie et al, 2012). These studies highlight the importance of specifying ASD subtypes when investigating neural biomarkers of ASD, considering the differences that are likely derived from the etiology of subgroups of ASD.…”