Association of MET with social and communication phenotypes in individuals with autism spectrum disorder.
Autism is a complex neurodevelopmental disorder diagnosed by impairments in social interaction, communication, and behavioral flexibility. Autism is highly heritable, but it is not known whether a genetic risk factor contributes to all three core domains of the disorder or autism results from the confluence of multiple genetic risk factors for each domain. We and others reported previously association of variants in the gene encoding the MET receptor tyrosine kinase in five independent samples. We further described enriched association of the MET promoter variant rs1858830 C allele in families with co-occurring autism and gastrointestinal conditions. To test the contribution of this functional MET promoter variant to the domains of autism, we analyzed its association with quantitative scores derived from three instruments used to diagnose and describe autism phenotypes: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS), and both the parent and the teacher report forms of the Social Responsiveness Scale (SRS). In 748 individuals from 367 families, the transmission of the MET C allele from parent to child was consistently associated with both social and communication phenotypes of autism. Stratification by gastrointestinal conditions revealed a similar pattern of association with both social and communication phenotypes in 242 individuals with autism from 118 families with co-occurring gastrointestinal conditions, but a lack of association with any domain in 181 individuals from 96 families with ASD and no co-occurring gastrointestinal condition. These data indicate that the MET C allele influences at least two of the three domains of the autism triad.
Campbell
Daniel B
DB
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.|Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.|Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.
Warren
Dana
D
Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.
Sutcliffe
James S
JS
Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
Lee
Evon Batey
EB
Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.|Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.
Levitt
Pat
P
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.|Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.|Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California.
D000483:Alleles; D001321:Autistic Disorder / Q000235:genetics; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007398:Interpersonal Relations; D008957:Models, Genetic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors
D005819:Genetic Markers; D019859:Proto-Oncogene Proteins c-met