Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women
We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 × 10–8) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 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.
These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.
We identified a novel association of AD with genetic variants in MGMT among women lacking the APOE ε4 allele in the ADGC cohorts and with genetic variants within and upstream of MGMT in Hutterite women regardless of APOE ε4 carrier status. Multi-omics analysis suggested that epigenetically regulated expression of MGMT, which is involved in DNA damage repair function, is significantly associated with the development of the hallmark AD proteins, Aβ and tau, especially in women. [Emphasis added]