Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Objective: We explored genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely small sub-cortical BI (SSBI), in eighteen population-based cohorts (N=20,949) from five ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in seven population-based cohorts (N=6,862, 1,483 with BI, 630 with SBBI), and tested associations with related phenotypes including ischemic stroke and pathologically-defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, P=1.77×10-8 and LINC00539/ZDHHC20, P=5.82×10-9. Both have been associated with blood pressure (BP) related phenotypes, but did not replicate in the smaller f...研究目的：本研究针对大型人群队列中磁共振成像（Magnetic Resonance Imaging, MRI）定义的脑梗死（Brain Infarcts, BI）的遗传与生活方式风险因素展开探索。 研究方法：我们开展了全基因组关联研究（Genome-Wide Association Studies, GWAS）的荟萃分析，并在来自5个种族的18个人群队列（总样本量20949例，其中脑梗死患者3726例、小型皮层下脑梗死（Small Sub-cortical BI, SSBI）患者2021例）中，检验了血管危险因素及其遗传风险评分（Genetic Risk Scores, GRS）与MRI定义的脑梗死及其亚型小型皮层下脑梗死的关联。随后，我们在7个人群队列（总样本量6862例，其中脑梗死患者1483例、小型皮层下脑梗死患者630例）中对筛选出的顶级关联位点进行了验证，并检验了这些位点与缺血性脑卒中、病理定义脑梗死等相关表型的关联。 研究结果：脑梗死的平均患病率为17.7%，小型皮层下脑梗死为10.5%，且患病率在65岁后呈急剧上升趋势。共有两个位点与脑梗死呈现全基因组显著关联：FBN2（P=1.77×10^-8）与LINC00539/ZDHHC20（P=5.82×10^-9）。上述两个位点均已被证实与血压（Blood Pressure, BP）相关表型存在关联，但在规模更小的队列中未得到重复验证（原文未完整表述）。