Epistatic Interactions for Brain eGWAS in Alzheimer's Disease

Nilufer Ertekin-Taner, Mayo Clinic

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It is well established that the risk for Alzheimer's disease (AD) is under substantial genetic control, and is thought to arise from multiple genetic variants and their interaction with each other. Such disease- associated variants can be identified using expression-based genome-wide association studies (eGWAS), based on the hypothesis that some AD risk variants will influence risk via their effects on brain gene expression. In this approach, gene expression levels are measured in the brain of autopsied AD subjects and those with other brain pathologies (control group). The expression level correlations with genetic variants are postulated to reveal novel genetic factors that influence disease risk including AD.

This project is dedicated to analyzing data from ~400 human subjects, measuring levels of ~24,000 transcripts that were part of an expression array. The brain gene expression levels of these transcripts were previously tested for association with 300,000 genetic variants. The gene expression measurements were done in two different brain regions: temporal cortex, and cerebellum. The subjects consisted of ADs and controls. In addition to main gene (or main variant) effects, there are also likely to exist epistatic effects that influence expression. This analysis seeks to identify sets of genes that act jointly to influence brain gene expression levels, and may therefore identify novel gene pairs or pathways that could have an effect on AD risk.