Sex‐specific DNA methylation differences associated with Alzheimer’s disease

Background Sex has increasingly been recognized as an important factor contributing to the heterogeneity in Alzheimer’s disease (AD). Method We performed a sex-specific meta-analysis of two large epigenome-wide association studies (ADNI, AIBL) blood, with total 633 and 651 samples females males, respecitively. For each dataset, we adjusted covariate variables age, sex, batch, immune cell-type proportions. The Inverse-variance fixed-effects model was then used prioritize most consistent DNAm differences across datasets. Result In female samples, 2 CpGs, mapped PRRC2A RPS8 genes, reached 5% false discovery rate (FDR). No CpGs FDR male analysis. At more relaxed significance threshold P < 1×10−5, additional 22 5 were identified respectively. these 29 AD-associated odds ratios ranged from 0.843 1.335 0.993 1.058 males. majority hypermethylated AD subjects (23 CpGs), located outside CpG islands or shores (27 distal regions greater than 2k bp TSS CpGs). Only gene promoters at SLC5A8 C16orf89. Sidak corrected P-value, our DMR analysis using comb-p software 49 distinct differentially methylated (DMRs) each. median numbers DMRs are 4 Among top 10 significant DMRs, about half them (6 females, males) AD. out promoter NNAT, CCDC169-SOHLH2, ARHGEF15, LPAR5, ZNF595 genes. MCCC1, PM20D1, PRR19, TTC23, LRRC28 Conclusion As sex is strong underlying phenotypic variability AD, results study particularly relevant for better understanding pathophysiology. They also provide valuable resource biomarkers drug targets