ABSTRACT

Previous genome-wide association studies (GWAS) have identified potential genetic variants involved in the risk of Alzheimer’s dementia, but their underlying biological interpretation remains largely unclear. In addition, the effects of DNA methylation and gene expression on Alzheimer’s dementia are not well understood. A network summary data-based Mendelian randomization (SMR) analysis was performed integrating cis- DNA methylation quantitative trait loci (mQTL) /cis- gene expression QTL (eQTL) data in the brain and blood, as well as GWAS summarized data for Alzheimer’s dementia to evaluate the pleiotropic associations of DNA methylation and gene expression with Alzheimer’s dementia and to explore the complex mechanisms underpinning Alzheimer’s dementia. After correction for multiple testing (false discovery rate [FDR] P < 0.05) and filtering using the heterogeneity in dependent instruments (HEIDI) test (P_HEIDI>0.01), we identified dozens of DNA methylation sites and genes showing pleiotropic associations with Alzheimer’s dementia. We found 22 and 16 potentially causal pathways of Alzheimer’s dementia (i.e., SNP→DNA methylation→Gene expression→Alzheimer’s dementia) in the brain and blood, respectively. Approximately two-thirds of the identified DNA methylation sites had an influence on gene expression and the expression of almost all the identified genes was regulated by DNA methylation. Our network SMR analysis provided evidence supporting the pleiotropic association of some novel DNA methylation sites and genes with Alzheimer’s dementia and revealed possible causal pathways underlying the pathogenesis of Alzheimer’s dementia. Our findings shed light on the role of DNA methylation in gene expression and in the development of Alzheimer’s dementia.

摘要

先前的全基因组关联研究 (GWAS) 已经确定了与阿尔茨海默病痴呆风险相关的潜在遗传变异，但其潜在的生物学解释仍不清楚。此外，DNA甲基化和基因表达对阿尔茨海默病痴呆的影响尚不清楚。整合大脑和血液中的顺式 DNA 甲基化数量性状位点 (mQTL) /顺式基因表达 QTL (eQTL) 数据以及阿尔茨海默病痴呆的 GWAS 汇总数据，进行了基于网络摘要数据的孟德尔随机化 (SMR) 分析评估 DNA 甲基化和基因表达与阿尔茨海默病痴呆的多效性关联，并探索支持阿尔茨海默病痴呆的复杂机制。多次测试校正后（错误发现率 [FDR] P< 0.05) 并使用依赖仪器中的异质性 (HEIDI) 测试 ( P _{HEIDI ) 进行过滤}>0.01)，我们确定了数十个 DNA 甲基化位点和基因，这些位点和基因显示出与阿尔茨海默病痴呆的多效性关联。我们分别在大脑和血液中发现了 22 和 16 种阿尔茨海默病痴呆的潜在致病途径（即 SNP→DNA 甲基化→基因表达→阿尔茨海默病痴呆）。大约三分之二的已鉴定 DNA 甲基化位点对基因表达有影响，几乎所有已鉴定基因的表达都受 DNA 甲基化的调节。我们的网络 SMR 分析提供了支持一些新的 DNA 甲基化位点和基因与阿尔茨海默病痴呆的多效性关联的证据，并揭示了阿尔茨海默病痴呆发病机制的可能因果途径。我们的研究结果揭示了 DNA 甲基化在基因表达和阿尔茨海默病痴呆发展中的作用。