Platform for Accelerating Genetic Discovery for Cerebrovascular Disease

 描述(申请人提供)：尽管中风在治疗和预防方面取得了实质性进展，但它仍然是全球第二大死亡原因，也是导致成年人严重残疾的主要原因。确定导致中风的脑血管疾病的生物学过程对于指导安全有效的治疗方法的开发至关重要。全基因组基因分型和测序成本的大幅下降使系统地收集关于个体基因组变异的大量数据成为可能。随着基因分型和测序技术的进步，描述患者特征的数据的可用性和复杂性大幅增加。在常规的临床评估中，经常会通过CT和MRI获得神经成像，现在可以使用在线工具全面确定中风亚型的分类，这些工具需要并保留来自医学评估的大量原始数据。最后，电子医疗记录现在保留了越来越多的参与研究的患者的数据。通过生成和分析全基因组的基因类型，并收集和分析数千名中风患者的广泛影像和表型数据，国际中风遗传学联合会(ISGC)在识别影响中风风险的遗传变异方面取得了实质性进展，这是发现周期的第一步。然而，利用这些和未来的数据来促进我们对脑血管疾病的理解和最终开发新的中风治疗靶点仍然存在实质性的障碍。数据集是(1)规模空前的，(2)位置不同的，(3)类型不同的。因此，研究界缺乏必要的数据访问和整合，以便进行有效和有力的比较，以生成新的假设并提高我们对脑血管疾病生物学的理解。我们建议创建新的基础设施，以广泛共享人类基因、表型和神经成像数据，以加速寻找有效的脑血管疾病治疗方法。加速脑血管疾病基因发现的平台将克服这三个障碍，为研究社区创建一个灵活且可扩展的资源，该资源整合了包含个人水平基因分型结果的基因数据集，纳入了从世界各地数十个中心收集的30,000多例中风病例和适当的非中风对照，所有这些都根据一个简化的方法进行了集中的质量控制，并通过伦理委员会批准的流程提供，以便与世界各地的任何研究人员快速共享。由中风遗传学的长期合作者组成的指导委员会管理，这个资源将改变人类中风的遗传学研究，提供一个持久的资源，最终可以通过ISGC建立的合作文化和使用该平台的研究人员的小额补贴来维持

 DESCRIPTION (provided by applicant): Despite substantial advances in its treatment and prevention, stroke remains the second-leading cause of death worldwide and the leading cause of major disability among adults. Identifying the biological processes that underlie the cerebrovascular diseases that cause stroke is crucial to guiding the development of safe and effective therapies. The dramatic fall in cost of genome-wide genotyping and sequencing has made it possible to systematically collect vast amounts of data on individual genome variation. In parallel with advances in genotyping and sequencing technology, there has been a substantial increase in the availability and complexity of data characterizing patients. Neuroimaging, via CT and often MRI, is very frequently obtained during routine clinical evaluation and classification of stroke subtype can now be comprehensively ascertained using online tools that require and retain large amounts of primary data from medical evaluations. Finally, electronic medical records now retain increasing amounts of data on patients enrolled in research studies. By generating and analyzing genome-wide genotypes and collecting and analyzing extensive imaging and phenotype data in thousands of individuals with stroke, the International Stroke Genetics Consortium (ISGC) has made substantial progress in identifying the genetic variants that influence risk of stroke, the initial step in the discovery cycle. Nonetheless, substantial barriers remain to leveraging these and future data for the advancement of our understanding of cerebrovascular disease and the ultimate development of novel therapeutic targets for stroke. Datasets are (1) of unprecedented scale, (2) disparate in location, and (3) heterogeneous in type. As a result, the research community lacks the data access and integration necessary in order to perform valid and well-powered comparisons to generate new hypotheses and improve our understanding of cerebrovascular disease biology. We propose to create new infrastructure for the wide sharing of human genetic, phenotypic and neuroimaging data for the purpose of accelerating the search for effective treatments for cerebrovascular disease. The Platform for accelerating genetic discovery for cerebrovascular disease will overcome these three barriers by creating a flexible and scalable resource for the investigative community that integrates genetic datasets containing individual-level genotyping results, incorporating over 30,000 stroke cases and appropriate stroke- free controls collected from dozens of centers around the world, all having undergone centralized quality control according to a single streamlined approach, and all made available through an ethics committee- approved process for rapid sharing with any investigator world-wide. Governed by a steering committee made up of long-standing collaborators in stroke genetics, this resource will transform the genetic study of stroke in humans, providing a durable resource that can ultimately be sustained by the established collaborative culture of the ISGC and small subsidies from researchers who utilize the Platform