Predictive utility of polygenic risk scores for chronic kidney disease.

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.