Published online March 2, 2009
PEDIATRICS Vol. 123 No. 3 March 2009, pp. 1018-1024 (doi:10.1542/peds.2008-0819)
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ARTICLE

Distinct Genetic Risk Based on Association of MET in Families With Co-occurring Autism and Gastrointestinal Conditions

Daniel B. Campbell, PhDa,b, Timothy M. Buie, MDc,d, Harland Winter, MDc,d, Margaret Bauman, MDc,d, James S. Sutcliffe, PhDb,e, James M. Perrin, MDc,d and Pat Levitt, PhDa,b

a Department of Pharmacology
b Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee
c Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
d Department of Pediatric Gastroenterology, Mass General Hospital for Children, Boston, Massachusetts
e Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee

OBJECTIVE. In addition to the core behavioral symptoms of autism spectrum disorder, many patients present with complex medical conditions including gastrointestinal dysfunction. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, we hypothesized that association of the autism spectrum disorder–associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions.

PATIENTS AND METHODS. Subjects were 918 individuals from 214 Autism Genetics Resource Exchange families with a complete medical history including gastrointestinal condition report. Genotypes at the autism spectrum disorder–associated MET promoter variant rs1858830 were determined. Family-based association test and {chi}2 analyses were used to determine the association of MET rs1858830 alleles with autism spectrum disorder and the presence of gastrointestinal conditions.

RESULTS. In the entire 214-family sample, the MET rs1858830 C allele was associated with both autism spectrum disorder and gastrointestinal conditions. Stratification by the presence of gastrointestinal conditions revealed that the MET C allele was associated with both autism spectrum disorder and gastrointestinal conditions in 118 families containing at least 1 child with co-occurring autism spectrum disorder and gastrointestinal conditions. In contrast, there was no association of the MET polymorphism with autism spectrum disorder in the 96 families lacking a child with co-occurring autism spectrum disorder and gastrointestinal conditions. {chi}2 analyses of MET rs1858830 genotypes indicated over-representation of the C allele in individuals with co-occurring autism spectrum disorder and gastrointestinal conditions compared with non-autism spectrum disorder siblings, parents, and unrelated controls.

CONCLUSION. These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.

Key Words: autism • genetics • gastrointestinal system • hepatocyte growth factor • HGF

Abbreviations: ASD—autism spectrum disorder • AGRE—Autism Genetic Resource Exchange • FBAT—family-based association test • TDT—transmission disequilibrium test

Accepted Jul 16, 2008.


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