Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies.
Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies.
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DOI：
10.1016/s1474-4422(16)00102-2
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发表时间：
2016-06
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通讯作者：
Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC)
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作者：
Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC)
中风是死亡和残疾的主要神经系统原因，人们对中风的遗传决定因素知之甚少，也很少在普通人群中进行探索。我们的目标是通过对全基因组关联研究进行荟萃分析来确定中风的其他位点。对于发现样本，我们对 18 个基于人群的队列（包括 84,961 名参与者，其中 4348 人患有中风）中与中风风险相关的常见遗传变异进行了全基因组分析。中风诊断由研究人员确定和验证。中风的平均年龄范围为 45·8 岁至 76·4 岁，研究中的数据收集发生在 1948 年至 2013 年之间。我们在最大的可用横断面研究（70 804 名参与者，其中 19 816 患有中风）。使用逆方差加权固定效应荟萃分析将发现和随访阶段的总结水平结果结合起来，并在中风亚型中进行计算机查找。对于全基因组的显着发现（p < 5 × 10−8），我们探索了与其他脑血管表型的关联，并使用小鼠中可能的因果基因的条件（诱导）删除进行了功能实验。我们还研究了这种可能的因果基因的直向同源物的表达及其对斑马鱼突变体脑血管系统的影响。我们复制了与缺血性中风风险相关的八个已知基因座中的七个，并在染色体 6p25 上发现了一个与全中风风险相关的新基因座（rs12204590，靠近 FOXF2）（比值比 [OR] 1·08，95% CI 1·05–1·12，p=1·48 × 10−8；次要等位基因频率 21%）。 rs12204590 中风风险等位基因还与无中风成人中 MRI 定义的白质高信号（脑小血管疾病的标志物）负担增加相关（n=21 079；p=0·0025）。一致的是，FOXF2 节段性缺失的年轻患者（2-32 岁）表现出广泛的白质高信号负担。成年小鼠中删除 Foxf2 会导致脑梗塞、反应性神经胶质增生和微出血。斑马鱼中FOXF2的直系同源物（foxf2b和foxf2a）在脑周细胞中表达，突变的foxf2b−/−脑血管显示平滑肌细胞和周细胞覆盖率降低。我们发现了 FOXF2 附近与中风易感性增加相关的常见变异。流行病学和实验数据表明，FOXF2 可能通过脑血管壁细胞的分化缺陷介导这种关联。需要在适当的人体组织中进行进一步的表达研究，并进行长期随访的进一步功能实验，以充分了解潜在的机制。
Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms.