International Meeting for Autism Research: Population- and Family-Based Studies Suggest An Epigenetic Role for the MTHFR Gene in the Etiology of Autism
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Population- and Family-Based Studies Suggest An Epigenetic Role for the MTHFR Gene in the Etiology of Autism

Saturday, May 22, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
10:00 AM
X. Liu , Department of Psychiatry, Queen's University, Kingston, ON, Canada
F. Solehdin , Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
I. L. Cohen , Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY
M. Gonzalez , Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY
E. C. Jenkins , Genetics, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY
S. M. Lewis , Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
J. J. A. Holden , Departments of Psychiatry & Physiology, ASPIRE, Queen's University, Kingston, ON, Canada
Background: Abnormal DNA methylation patterns have been associated with neurodevelopmental disorders, including autism. Two variants in the methylenetetrahydrofolate reductase (MTHFR) gene have previously been shown to affect DNA methylation levels, and both have been shown to be associated with autism susceptibility in case-control studies.

Objectives: Test for association between two functional SNPs in the MTHFR gene with autism spectrum disorders (ASDs).

Methods: The C677T (rs1801133) and A1298C (rs1801131) polymorphisms were studied in 205 North American families with a single child with an ASD (simplex: SPX). Both family-based and case-control association studies were performed.

Results: Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele (P=0.0004), higher prevalence of the 677TT genotype (P=0.0016), marginally higher frequency of the 1298A allele (P=0.059) and a trend towards increased prevalence of the 1298AA genotype (P=0.124) in autistic probands from SPX families versus controls. Analysis of combined genotypes revealed a significantly higher frequency of the double homozygous 677TT/1298AA genotype (P=0.007) and the 677T-1298A haplotype (P=0.0004) in affected individuals relative to controls. Family-Based Association Testing (FBAT) demonstrated significant transmission disequilibrium of both SNPs, with an excess transmission of the 677T (P=6.5 X 10-5) and 1298A (P=0.015) alleles and the 677T-1298A haplotype (P=9.1 X 10-5) from parents to affected offspring.

Conclusions: The results of both the population-based and family-based studies suggest that reduced MTHFR activity serves as an epigenetic risk factor for autism in families with isolated cases.

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