Neurosciences des Croyances

Linking DNA methylation in brain regions to Alzheimer's disease risk: a Mendelian randomization study.

Zhong H, Zhu J, Liu S, Zhou D, Long Q, Wu C, Zhao B, Cheng C, Yang Y, Wu Q, Wu Y, Li C, Wang Z, Wu J, Guo X, Zhi D, Deng Y, Wu L

Hum Mol Genet . 2025;34 (12) :1026-1033

📅 04/06/2025 PMID : 40267236 DOI : 10.1093/hmg/ddaf053

Résumé

AIM: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.METHODS: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). In our MR analyses, we integrated these mQTLs with single nucleotide polymorphisms (SNP)-ad risk summary statistics derived from 85 934 ad-related cases and 401 577 normal controls.RESULTS: Among 62 554 cytosine-guanine dinucleotide (CpG) sites, we identified 597 CpG sites (CpGs) significantly associated with ad risk (false discovery rate (FDR)