Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer disease among women.

Abstract

Increasing evidence suggests epidemiological and pathological links between Alzheimer disease (AD) and breast cancer (BC). The 17q21 locus, including MAPT encoding tau, has been identified in genome-wide association studies (GWAS) for BC in women and AD among persons lacking the APOE ε4 allele (ε4-). We hypothesized that other genes involved in tau-related pathology can be identified by GWAS in women stratified by ε4 status. We conducted a GWAS for AD among ε4- women (3,400 AD and 6,940 controls) in Alzheimer's Disease Genetics Consortium (ADGC) datasets and separately analyzed whole genome sequencing data obtained from five AD cases (all women; ε4+=4) and 26 controls (17 women, 9 men; ε4+=9) in a Hutterite kindred from South Dakota. Association tests were performed using logistic regression with covariates for age and principle components of ancestry in the ADGC datasets and for age, sex, and ε4 in the Hutterites. Potential mechanisms of top-ranked findings were investigated by integrating omics data including gene expression, DNA-methylation (DNAm), and AD-related neuropathological traits in subsets stratified by sex and ε4 status in the Religious Orders Study and Memory and Aging Project (ROSMAP; 339 AD and 229 controls). We identified genome-wide significant associations with one novel locus MGMT in each sample (ADGC: rs12775171, odds ratio [OR]=1.4, P=4.9x10-8 ; Hutterites: rs12256016, OR=2.0, P=1.9x10-14 ). Rs12775171 showed no evidence of association with AD risk in ε4+ women or in men in the ADGC datasets (P>0.05). Rs12775171 is not in linkage disequilibrium with rs12256016. At least one of these SNPs was significantly associated with increased DNAm levels near/within MGMT (best association pair: rs11016864 [proxy for rs12256016] with cg01419164; P=4.0x10-4 in women), which were also significantly associated with lower MGMT expression (P=0.03) and worse tau burden in all AD cohorts (neurofibrillary tangle; P=6.0x10-3 ), women (Braak stage; P=4.0x10-3 ), and ε4- women (neurofibrillary tangle; P=0.03), but not among ε4+ women, all men, or ε4+/ε4- men in ROSMAP. We identified a novel association of AD with the interaction of sex and MGMT. Our omics analysis confirmed that epigenetically regulated expression of MGMT (involved in DNA methylation damage repair) is significantly associated with tau in women.