Zhong Hua, Zhu Jingjing, Liu Shuai, Zhou Dan, Long Quan, Wu Chong, Zhao Bingxin, Cheng Chao, Yang Yaohua, Wu Qing, Wu Yong, Li Changwei, Wang Zhaoming, Wu Jianyong, Guo Xingyi, Zhi Degui, Deng Youping, Wu Lang
Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, 701 Ilalo St, Honolulu, HI 96813, United States.
Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawai'i at Mānoa, 651 Ilalo Street, Honolulu, HI 96813, United States.
Hum Mol Genet. 2025 Apr 23. doi: 10.1093/hmg/ddaf053.
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.
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.
Among 62 554 cytosine-guanine dinucleotide (CpG) sites, we identified 597 CpG sites (CpGs) significantly associated with ad risk (false discovery rate (FDR) < 0.05). Of these, 289 were confirmed through colocalization and summary-based MR (SMR) analyses, including one CpG site in CRBLM, 285 in DLPFC, one in FCTX, two in PONS, and one in TCTX. By integrating gene expression data, we identified 19 CpG sites with consistent associations across methylation levels, expression of eight target genes, and ad risk, including novel regulatory mechanisms involving RITA1's modulation of cg11558705 and PCGF3's regulation of cg10009224.
Our findings highlight brain region-specific DNA methylation as a mediator of genetic risk for ad, offering insights into ad pathogenesis and identifying potential therapeutic targets.
脑区中的DNA甲基化代表了一种将基因变异与阿尔茨海默病（AD）风险联系起来的潜在机制，但大多数研究都集中在血液来源的甲基化标记上。在本研究中，我们进行了一项系统性孟德尔随机化（MR）研究，以评估预测的脑区特异性DNA甲基化水平与AD风险之间的关联，使用甲基化数量性状位点（mQTL）作为遗传工具。
我们分析了来自吉布斯等人研究中600名个体的五个脑区（小脑（CRBLM）、额叶皮质（FCTX）、脑桥（PONS）和颞叶皮质（TCTX））的mQTL，以及宗教秩序研究和拉什记忆与衰老项目（ROSMAP）中543名参与者的背外侧前额叶皮质（DLPFC）的mQTL。在我们的MR分析中，我们将这些mQTL与来自85934例AD相关病例和401577例正常对照的单核苷酸多态性（SNP）-AD风险汇总统计数据相结合。
在62554个胞嘧啶-鸟嘌呤二核苷酸（CpG）位点中，我们鉴定出597个与AD风险显著相关的CpG位点（错误发现率（FDR）<0.05）。其中，289个通过共定位和基于汇总的MR（SMR）分析得到证实，包括CRBLM中的1个CpG位点、DLPFC中的285个、FCTX中的1个、PONS中的2个和TCTX中的1个。通过整合基因表达数据，我们鉴定出19个在甲基化水平、八个靶基因的表达和AD风险方面具有一致关联的CpG位点，包括涉及RITA1对cg11558705的调节和PCGF3对cg10009224的调节的新调控机制。
我们的研究结果突出了脑区特异性DNA甲基化作为AD遗传风险的介导因素，为AD发病机制提供了见解，并确定了潜在的治疗靶点。
