A genetic variant that disrupts MET transcription is associated with autism

There is strong evidence for a genetic predisposition to autism, and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family-based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here we show genetic association (P=0.0005) of a common ‘C’ allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P=0.001) and in the combined sample (P=0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P=0.000007). In case-control analyses, the relative risk of the ‘CC’ genotype was 2.26 (95% confidence interval: 1.41, 3.63) compared to the ‘GG’ genotype. Functional assays showed that the ‘C’ allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate altered MET gene expression in autism susceptibility, providing evidence of a novel pathophysiological basis for this behaviorally and medically complex disorder.