Genome‐wide association and multi‐omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women

Introduction Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E epsilon 4 (epsilon 4-). Methods To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 epsilon 4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred. Results We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 x 10(-8)) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 x 10(-14)) datasets. Multi-omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression, and AD-related neuropathological traits were observed among women. Furthermore, promoter capture Hi-C analyses revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites. Discussion These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.