Integrative Genomic Approaches for Understanding Sex Differences in AD

Funding: R01AG062634  PIs: Martin ER, Kunkle BW, Wang L

Women make up nearly two-thirds of all Alzheimer's disease (AD) cases in the United States and these differences are likely due to contributions from differential genetic and environmental effects between the sexes. While several candidate gene studies have identified sex-specific associations, no large-scale, genome- wide, sex-specific association analysis of AD has been conducted. Furthermore, the functional underpinnings of sex-specific genetic associations and how they relate to expression and epigenetic variations, are still largely unknown.

We hypothesize that multiple genetic, epigenetic and gene-expression changes operate in a sex-specific manner to explain at least part of the sex disparity in AD prevalence. To this end, we propose new strategies for integrative analysis of DNA variants, gene expression, splicing and DNA methylation in a sex- aware framework, which will allow us to prioritize variants with the most regulatory potential and provide additional insight into the biological mechanisms of sex differences in AD. To accomplish these goals we will leverage existing large-scale genetic data from several consortia studies in AD, as well as expression and methylation data from brain tissue of AD cases and healthy individuals.