A comprehensive approach to understanding the genetic causes of urinary stone disease: combining monogenic and polygenic analyses

Project Summary/Abstract Title: A comprehensive approach to understanding the genetic causes of urinary stone disease: combining monogenic and polygenic analyses One in eight Americans is affected by Urinary Stone Diseases (USDs), with 52% of them experiencing recurrence within 10 years. Despite their high prevalence, our understanding of the underlying mechanisms of stone formation remains incomplete. USDs are thought to result from a combination of genetics and environmental factors. Genetic studies have identified 51 monogenic causes, accounting for 11-20% of pathogenesis. The heritability of USDs is estimated to be 45-50%. We hypothesize that there are additional novel monogenic and polygenic causes, as well as gene-gene (GxG) interactions, contributing to the pathogenesis of USDs. With this in mind, we plan to systematically investigate both monogenic and polygenic genes to identify novel variants associated with USDs. To accomplish this, we will perform whole genome sequencing and whole exome sequencing analyses on patients recruited from Harvard Medical School and NIH's "All of Us" project. We will also conduct GxG analysis to analyze the relationship between the risk loci and monogenic genes and develop a polygenic risk score (PRS) for USDs. Furthermore, we will integrate the burden analysis from monogenic genes into PRS to develop a mono-polygenic risk score (MPRS) for clinical and research use. Our goal is to employ this comprehensive approach to gain a deeper understanding of USDs, facilitating future precision pharmaceutical or environmental interventions. This K08 grant proposal also outlines a five-year plan for the development of Dr. Chen-Han Wilfred Wu, MD, PhD, into an independent physician-scientist specializing in Urology and Genetics. Dr. Wu has had a unique interdisciplinary training in Urology and Genetics, and he will continue to strive forward as a uro-genetics researcher by gaining additional expertise in both monogenic and polygenic approaches, epidemiology and biostatistics, and integrating physiology and functional studies with genetics. Through a structured mentorship plan, multiple advisory committees, coursework, and conferences, Dr. Wu will gain the necessary skills to advance his career as a physician-scientist. Under the guidance of Dr. Friedhelm Hildebrandt, MD, an esteemed expert in monogenic studies, and Dr. Fredrick Schumacher, PhD, MPH, a respected statistical geneticist, Dr. Wu is firmly committed and passionately devoted to advancing science and medicine to improve patient care as a physician-scientist.