Predictive utility of polygenic risk scores for chronic kidney disease.

摘要 在这份申请为期5年的K25职业发展奖的申请书中，我建议进行一项有指导的研究和职业 发展计划，为未来肾脏疾病独立研究人员的职业生涯奠定基础。 本研究项目的目标是开发和测试慢性肾脏疾病(CKD)的多基因风险评分。 及其肾小球亚型，如免疫球蛋白A肾病(IgAN)、膜性肾病(MN) 局灶节段性肾小球硬化(FSGS)。尽管传统上基因研究主要集中在 在与疾病高风险相关的罕见基因变异上，有越来越多的证据表明，普通变异 对常见慢性病的风险有很大的多基因贡献，这些发现可能 对公众健康有重大影响。最近的研究表明，多基因风险最高的1%-5%的人 得分分布的疾病风险相当于目前临床测试的许多罕见变种，包括 导致肥胖、乳腺癌、结肠癌、炎症性肠病、 心房颤动，或冠状动脉疾病。例如，BMI的全基因组多基因风险分数是 开发和验证，使用210万个常见的遗传变异来准确预测 生命早期的严重肥胖。这项建议将使用类似的方法来评估多基因对慢性肾脏病的贡献。 以及它的各种亚型，对于这些亚型，新的强大的全基因组关联研究(GWAS)数据集是 目前正在从我们的实验室中脱颖而出(我是大多数研究的共同作者，通过贡献来自Emerge和 英国生物库财团)。在导师的指导下，我起草了一份5年职业发展计划， 包括关于肾脏疾病及其亚型的临床领域知识的培训，包括熟悉 常见肾脏疾病的发病机制模型及多基因评分的临床应用 肾病学(主要导师：Krzysztof Kiryluk博士)、生物医学信息学(联合导师：翁春华博士)和 用于分析多维遗传和表型数据的新的统计遗传学方法(尤利安娜博士 Ionita-Laza)。在奖项的最后两年，我将申请R01资金并过渡到独立。这个 拟议的活动将使我做好准备，进行以患者为导向的生物医学研究，以发现新的基因 慢性肾脏病的危险因素及早期诊断策略。

ABSTRACT In this application for a 5-year K25 Career Development Award, I propose a mentored research and career development plan providing a foundation for a future career as an independent investigator in kidney disease. The goal of this research project is to develop and test polygenic risk scores for chronic kidney disease (CKD) and its glomerular subtypes, such as immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although traditionally genetic studies have been focused largely on rare genetic variants associated with a high risk of disease, there is mounting evidence that common variants have substantial polygenic contributions to the risk for common chronic diseases and these findings may have a significant public health impact. Recent studies demonstrate that individuals in the top 1-5% of polygenic risk score distribution have disease risk equivalent to many of the rare variants currently tested for clinically, including mutations that are causal for diseases such as obesity, breast cancer, colon cancer, inflammatory bowel disease, atrial fibrillation, or coronary artery disease. For example, a genome-wide polygenic risk score for BMI has been developed and validated that uses 2.1 million common genetic variants to accurately predict the development of severe obesity early in life. This proposal will apply similar methods to evaluate polygenic contributions to CKD and its various subtypes for which new powerful genome-wide association studies (GWAS) datasets are presently emerging from our lab (I am co-author of most of the studies by contributing data from eMERGE and UK biobank consortia). With guidance from my mentors, I have drafted a 5-year career development plan that includes training in clinical domain knowledge of kidney disease and its subtypes including familiarity with the pathogenesis models for common kidney disorders and potential clinical applications of polygenic scores in nephrology (primary-mentor: Dr. Krzysztof Kiryluk), biomedical informatics (co-mentor: Dr. Chunhua Weng) and novel statistical genetics methods for the analysis of multidimensional genetic and phenotypic data (Dr. Iuliana Ionita-Laza). In the last two years of the award I will apply for R01 funding and transition to independence. The proposed activities will prepare me to conduct patient-oriented and biomedical research to discover novel genetic risk factors for CKD and early diagnosis strategies for CKD and its major subtypes.