A genetic variant that disrupts MET transcription is associated with autism
- Daniel B. Campbell*,
- James S. Sutcliffe†,‡,
- Philip J. Ebert*,
- Roberto Militerni§,
- Carmela Bravaccio§,
- Simona Trillo¶,
- Maurizio Elia‖,
- Cindy Schneider**,
- Raun Melmed††,
- Roberto Sacco‡‡,§§,
- Antonio M. Persico‡‡,§§, and
- Pat Levitt*,‡,¶¶
- *Departments of Pharmacology and
- †Molecular Physiology and Biophysics and
- ‡Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37203;
- §Department of Child Neuropsychiatry, Il University of Naples, I-80131 Naples, Italy;
- ¶Associazione Anni Verdi ONLUS, 00148 Rome, Italy;
- ‖Unit of Neurology and Clinical Neurophysiopathology, Scientific Institutes for Research, Hospitalization and Health Care (IRCCS) Oasi Maria SS, 94018 Troina, EN, Italy;
- **Center for Autism Research and Education, Phoenix, AZ 85012;
- ††Southwest Autism Research and Resource Center, Phoenix, AZ 85006;
- ‡‡Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, I-00155 Rome, Italy; and
- §§IRCCS Fondazione Santa Lucia, 00179 Rome, Italy
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Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved September 1, 2006 (received for review June 23, 2006)
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.
Footnotes
- ¶¶To whom correspondence should be addressed. E-mail: pat.levitt{at}vanderbilt.edu
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Author contributions: D.B.C., P.J.E., A.M.P., and P.L. designed research; D.B.C. performed research; J.S.S., R. Militerni, C.B., S.T., M.E., C.S., and R. Melmed contributed new reagents/analytic tools; D.B.C., J.S.S., R.S., and A.M.P. analyzed data; and D.B.C., J.S.S., P.J.E., A.M.P., and P.L. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS direct submission.
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See Commentary on page 16621.
- Abbreviations:
- FBAT,
- family based association test;
- HBAT,
- haplotype-based association test;
- LD,
- linkage disequilibrium;
- TEXP,
- transmissions expected;
- TOBS,
- transmissions observed.
- © 2006 by The National Academy of Sciences of the USA
