An Integrated Genetic and Epigenetic Approach to Cerebral Small Vessel Disease

描述（由申请人提供）：脑血管病（SVD）包括一系列影响大脑小血管的病理。SVD的表现包括磁共振成像（MRI）可检测到的脑实质内的异质性病变。特别是，白质高强度（WMH）是老年人大脑中常见的病变，被广泛认为是中风、痴呆和死亡率的重要预测因子。遗传因素和高血压是SVD的主要危险因素，全基因组关联研究最近发现了WMH的新位点。然而，这些位点上的常见变异只能解释表型变异的一小部分遗传贡献。残余遗传变异或“缺失遗传力”有几种可能的来源，包括罕见的序列变异和表观遗传变异。然而，这两种变异源对SVD风险及其相关合并症的影响尚未得到广泛探讨。我们假设基因型、表观基因型和风险因素暴露之间的相互作用是SVD病因学的基础，并提出了一个综合分析框架来确定这种关系。拟议的项目将利用社区动脉粥样硬化风险研究、心血管健康研究、弗雷明汉心脏研究和鹿特丹研究的4个基于人群的前瞻性队列资源：(1)使用已收集的5000多名脑部MRI参与者的全外显子组序列（WES）数据，对MRI定义的脑SVD进行全外显子组关联分析；(2)对mri定义的脑SVD进行血液甲基组关联分析；(3)发现新的血液甲基组特征，介导mri定义的SVD与高血压暴露之间的因果关系；(4)研究遗传和表观遗传变异的联合信息是否能预测临床事件的易感性，包括缺血性脑卒中和痴呆。

DESCRIPTION (provided by applicant): Cerebral small vessel disease (SVD) encompasses a spectrum of pathologies that affect the small vessels of the brain. Manifestation of SVD includes heterogeneous lesions in the brain parenchyma detectable by magnetic resonance imaging (MRI). In particular, white matter hyperintensities (WMH) are commonly-identified lesions in the elderly brain and are widely recognized as a significant predictor of stroke, dementia, and mortality. Genetic factors and hypertension are major risk factors of SVD and genome-wide association studies have recently identified novel loci for WMH. Yet, the common variants at these loci explain only a fraction of the genetic contribution to the phenotypic variance. There are several possible sources of the residual genetic variance or "missing heritability", including rare sequence variation and epigenetic variation. However, the contribution of these two sources of variation to SVD risk and its associated comorbidities has not been widely explored. We hypothesize that the interplay between genotype, epigenotype, and risk factor exposure underlies SVD etiology and propose an integrated analytic framework to identify such relationships. The proposed project will use the resources of the 4 large population-based, prospective cohorts of the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, the Framingham Heart Study and the Rotterdam Study to (1) conduct whole-exome association analyses of MRI-defined cerebral SVD using already-collected whole exome sequence (WES) data on over 5000 participants with a brain MRI; (2) conduct blood methylome association analyses of MRI-defined cerebral SVD; (3) identify novel blood methylome signatures that mediate the causal relationships between MRI-defined SVD and exposure to high blood pressure; and (4) investigate whether the combined information on genetic and epigenetic variation predicts susceptibility to clinical events, including ischemic stroke and dementia.