title: A genetic variant that disrupts MET transcription is associated with autism.
abstract: 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 autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with 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 reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.
authors.affiliation: Department of Pharmacology, Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37203, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Campbell
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Ebert
authors.forename: Roberto
authors.initials: R
authors.lastname: Militerni
authors.forename: Carmela
authors.initials: C
authors.lastname: Bravaccio
authors.forename: Simona
authors.initials: S
authors.lastname: Trillo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Elia
authors.forename: Cindy
authors.initials: C
authors.lastname: Schneider
authors.forename: Raun
authors.initials: R
authors.lastname: Melmed
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
mesh_terms: D000483:Alleles; D001321:Autistic Disorder / Q000209:etiology / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004247:DNA / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D004247:DNA; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met