Genetics of Early-Onset Ischemic Stroke Consortium

在美国，缺血性中风是第四大致死原因，也是致残的主要原因。该病的病因学 中风是多因素的，人们对此知之甚少。遗传学是一种潜在的强大工具，可以更好地理解 疾病病因学，因为它可以突出疾病背后的生物机制，并指明改进的方向 预防和治疗。破译缺血性中风的遗传基础的努力一直是 因为它的异质性而受到阻碍。我们的研究通过关注早发性来解决这个问题 缺血性中风(即发病60岁)，中风的一种特别破坏性的表现，因为它对 养育孩子和工作能力。早发性缺血性中风约占所有首次中风的20%， 这一比例正在上升。研究其他常见遗传病的早期发病形式(如癌症、 心脏病、糖尿病)为疾病病因学提供了有价值的见解，因为 遗传因素。我们的总体假设是，早发性缺血性中风的遗传信号丰富 可强调中风潜在的生物机制，并指明改善预防和治疗中风的方法 治疗策略。虽然在研究早发性缺血性中风方面的潜在效用一直很好 认识到，一个主要的限制是累积大样本量。我们已经迈出了一大步， 通过联合多中心早发性卒中克服样本量不足的主要限制 遗传学联盟，包括多达13,500名已经对常见和罕见变异进行基因分型的病例， 后者允许我们测试令人信服的假说，评估低频变异对早期- 发作性中风易感性。 我们研究的主要目标是发现与早发有关的常见和罕见的变异 通过对多达13,500名早期患者的GWA和外显子组阵列的全基因组关联分析，得出了缺血性卒中的结论 发病的缺血性中风病例和来自16个参与队列的94,000名对照。对于新发现的 中风相关基因座，我们将使用多种生物信息学识别因果变异、基因和途径 接近了。我们还将确定新发现的中风相关基因是否也与 发病年龄较大的中风，以及反映血栓前活动的血清生物标记物水平。最后，我们将测试 使用多基因风险评分和深静脉血栓形成之间的遗传风险共享 LD回归。 新途径和药物靶点的成功识别有可能改变我们的 了解中风的病理生理学，并导致更有效的预防策略。我们的研究将 利用早发性病例的优势进行遗传学研究，也将是最有力的 到目前为止，检查罕见变异在早期发病中的作用是病因学。拟议的研究将建立一个 为继续研究IS的遗传基础提供独特的资源，补充老年人的研究。

Ischemic stroke is the 4th leading cause of death in the U.S. and a major cause of disability. The etiology of stroke is multifactorial and poorly understood. Genetics is a potentially powerful tool for better understanding disease etiology as it can highlight biological mechanisms underlying disease and point the way to improved prevention and treatment. Efforts to decipher the genetic underpinnings of ischemic stroke have been hampered because of its heterogeneity. Our study addresses this problem by focusing on early-onset ischemic stroke (i.e., onset < 60 years), a particularly devastating manifestation of stroke because of its toll on child rearing and the ability to work. Early-onset ischemic stroke comprises ~ 20% of all first-ever stroke and this proportion is increasing. Studying early onset forms of other common genetic diseases (e.g., cancers, heart disease, diabetes) has provided valuable insights about disease etiology because of the enrichment of genetic causes. Our overall hypothesis is that early-onset ischemic stroke is enriched for genetic signals that may highlight biological mechanisms underlying stroke and point the way to improved prevention and treatment strategies. While the potential utility in studying early-onset ischemic stroke has been well recognized, a major limitation has been the accrual of large sample sizes. We have taken a large step to overcome the primary limitation of insufficient sample size by pulling together a multicenter early-onset stroke genetics consortium that includes up to 13,500 cases already genotyped for common and rare variants, the latter allowing us to test compelling hypotheses assessing the contribution of low frequency variants to early- onset stroke susceptibility. The primary goals of our study are to detect common and rare variants associated with early-onset ischemic stroke through genome-wide association analysis of GWAS and exome arrays in up to 13,500 early- onset ischemic stroke cases and 94,000 controls from 16 participating cohorts. For the newly discovered stroke-associated loci, we will identify causal variants, genes, and pathways using multiple bioinformatics approaches. We will also determine if the newly discovered stroke-associated loci are also associated with older onset stroke and with serum levels of biomarkers reflective of prothrombotic activity. Finally, we will test for shared genetic risk between early-onset IS and deep venous thrombosis using polygenic risk scores and LD regression. The successful identification of novel pathways and drug targets has the potential to transform our understanding of the stroke pathophysiology and lead to more effective preventive strategies. Our study will leverage the advantages of early-onset IS cases for genetic studies, and will also be the most well-powered examination to date of the role of rare variants in early onset IS etiology. The proposed study will establish a unique resource for continued studies of the genetic basis of IS, complementary to studies in older adults.