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.
