Genetics of Early-Onset Ischemic Stroke Consortium

缺血性中风是美国第四大死亡原因，也是残疾的主要原因。的病因 中风是多因素的，但人们对它了解甚少。遗传学是一个潜在的强大工具， 疾病病因学，因为它可以突出疾病的生物学机制，并指出改善 预防和治疗。破译缺血性中风的遗传基础的努力已经 由于其异质性而受到阻碍。我们的研究通过关注早发性 缺血性中风（即，发病< 60岁），这是中风的一种特别具有破坏性的表现，因为它对 抚养孩子和工作能力。早发性缺血性卒中占所有首次卒中的约20%， 这一比例正在增加。研究其他常见遗传疾病的早期发病形式（例如，癌症， 心脏病，糖尿病）提供了关于疾病病因学的有价值的见解， 遗传原因。我们的总体假设是早发性缺血性卒中富含遗传信号， 可能会突出中风的生物学机制，并指出改善预防的方法， 治疗策略。虽然研究早发性缺血性卒中的潜在效用已经很好， 人们认识到，一个主要的限制是大样本量的累积。我们迈出了一大步， 通过整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例已经基因分型的常见和罕见变异， 后者使我们能够测试令人信服的假设，评估低频变异对早期- 中风易感性 我们研究的主要目的是检测与早发性乳腺癌相关的常见和罕见变异， 缺血性卒中通过GWAS和外显子组阵列的全基因组关联分析，在多达13，500例早期 来自16个参与队列的94，000例缺血性卒中病例和对照。对于新发现的 中风相关的基因座，我们将确定因果变异，基因和途径，使用多种生物信息学 接近。我们还将确定新发现的卒中相关基因座是否也与 老年发作的中风和反映血栓前活性的生物标志物的血清水平。最后，我们将测试 使用多基因风险评分确定早发性IS和深静脉血栓形成之间共有的遗传风险， LD回归 新的途径和药物靶点的成功鉴定有可能改变我们的研究。 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IS病例的优势进行遗传学研究，也将是最有说服力的 迄今为止对罕见变异体在早发性IS病因学中的作用的研究。拟议的研究将建立一个 持续研究IS遗传基础的独特资源，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.