Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10−8), was associated with F2 expression in blood (P = 6.4 × 10−5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.

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MRI 脑白质高信号的表观遗传学和综合跨组学分析

MRI 上的脑白质高信号是脑小血管疾病的标志，而脑小血管疾病是痴呆和中风的主要危险因素。尽管成功鉴定了与这种高度遗传性疾病相关的多种遗传变异，但其遗传结构仍不完全清楚。更具体地说，DNA 甲基化的作用很​​少受到关注。我们调查了来自 14 项社区研究的 9,732 名中老年人的白质高信号负荷与血液中大约 450,000 个 CpG 位点的 DNA 甲基化之间的关联。进行了单 CpG 和基于区域的关联分析。进行功能注释和综合跨组学分析，以确定 DNA 甲基化和白质高信号之间关系的新基因。我们确定了 12 个单 CpG 和 46 个基于区域的 DNA 甲基化与白质高信号负荷的关联。我们最重要的发现单个 CpG，cg24202936 (P = 7.6 × 10−8)，与血液中的 F2 表达相关 (P = 6.4 × 10−5)，并与大脑中的 FOLH1 表达共定位（后验概率 =0.75）。我们的最高差异甲基化区域位于 PRMT1 和 CCDC144NL-AS1 中，它们也代表在单 CpG 关联中（分别为 cg17417856 和 cg06809326）。通过孟德尔随机分析，cg06809326 被推定与白质高信号负担相关（P = 0.03），并且 CCDC144NL-AS1 的表达可能介导这种关联。差异甲基化区域分析、联合表观遗传关联分析和多组学共定位分析一致确定了 SH3PXD2A 附近 DNA 甲基化的作用，SH3PXD2A 是先前在白质高信号全基因组关联研究中发现的一个位点。基因集富集分析揭示了已识别的 DNA 甲基化位点在血脑屏障和免疫反应中的功能。综合跨组学分析确定了两个与细胞外基质组织、脂质和脂蛋白代谢相关的网络中的 19 个关键调控基因。药物重新定位分析表明抗高脂血症药物，更具体地说是过氧化物酶体增殖物激活受体α，可能是治疗白质高信号的靶药物。我们的全表观基因组关联研究和综合跨组学分析表明影响白质高信号负担的新基因，这些基因集中在与免疫反应和血脑屏障受损相关的途径上，这可能是由于细胞-细胞和细胞-细胞外基质相互作用破坏所致。结果还表明，降脂治疗可能通过防止血脑屏障破坏而有助于降低白质高信号的风险。