Genome-wide examination of DNA methylation in autism

Active

Fallin, Dani

Johns Hopkins University

$449,998.01

3 years

Basic & Clinical

Baltimore

MD

United States

2011

http://www.jhu.edu

City: 
Baltimore
State/Province: 
MD
State/Province Full: 
Maryland
Country: 
United States

Previous studies have estimated that autism (ASD) is highly heritable, i.e., many of ASDs clinical attributes can be explained by genetics. However, no single causal gene has yet been identified. Although several genetic variants are associated with autism, they account for a relatively small proportion of the estimated heritability and none has been definitively confirmed. This paradox may be explained by the inter-dependency between particular genetic sequences and specific environmental exposures, often referred to as gene-environment interaction (GxE). Growing evidence suggests environmental exposures, especially prenatal, are risk factors for autism. Thus, it is important to examine genetic variation in the context of environmental exposures and to identify potential mechanisms for GxE in autism. This is the primary objective of the current study. Although every cell in the human body has essentially the same DNA sequence, they have very different and specific functions. Cell type-specific functions arise from different sets of genes being turned on or off, i.e., cells run different gene expression programs. DNA methylation (DNAm), a reversible chemical modification of DNA, is a way for cells to regulate their gene expression program without changing their DNA sequence. There is growing evidence that DNAm is susceptible to environmental exposures, providing a physical link between environmental risk factors and genetics. Identification of DNAm differences (whether due to genetic or environmental factors) among children with and without ASD may elucidate a biological mechanism for GxE in ASD. The investigators will measure DNAm across the genome of 600 children (300 with ASD and 300 without) from The Study to Explore Early Development. The specific aims are to: 1) measure DNAm across the genome and identify differences based on (a) diagnosis, (b) genetic sequence, (c) prenatal environmental exposures, and (d) sites of GxE; 2) confirm prior findings using an independent method and set of samples; and 3) establish tissue-relevance by comparing prior results (from blood) to DNAm patterns obtained in a parallel study of brains from 30 ASD and 30 non-ASD individuals. Integration of genetic, DNAm, and environmental information enables the first comprehensive molecular analysis of potential GxE in autism, and may also identify modifiable risk factors and provide new diagnostic and therapeutic targets for ASD.