The Genetic Architecture of Structural Renal and Urinary Tract Malformations

Structural renal and urinary tract malformations are the most common cause of kidney failure in children. These congenital anomalies of the kidneys and urinary tract (CAKUT) are a phenotypically diverse group of malformations that result from defects in embryonic kidney, ureter, and bladder development. A genetic basis for CAKUT has been proposed, with over 50 monogenic causes reported, however, a molecular diagnosis is detected in less than 20% of patients. In this thesis, I used bioinformatics and statistical genetics methodology to investigate the genetic architecture of structural renal and urinary tract malformations using whole-genome sequencing (WGS) data from the 100,000 Genomes Project. Population-based rare and common variant association testing was performed in over 800 cases and 20,000 controls of diverse ancestry seeking enrichment of single-nucleotide/indel and structural variation on a genome-wide, per-gene, and cis-regulatory element basis. Using a sequencing-based genome-wide association study (GWAS) I identified the first robust genetic associations of posterior urethral valves (PUV), the most common cause of kidney failure in boys. Bayesian fine-mapping and functional annotation mapped these two loci to the transcription factor TBX5 and planar cell polarity gene PTK7, with both signals replicated in an independent cohort. Significant enrichment of rare structural variation affecting cis-regulatory elements was also detected providing novel insights into the pathogenesis of this poorly understood disorder. I also demonstrated that the contribution of known monogenic disease to CAKUT has been overestimated and that common and low-frequency variation plays an important role in phenotypic variability. These findings support an omnigenic rather than monogenic model of inheritance for CAKUT and are consistent with the extensive genotypic-phenotypic heterogeneity, variable expressivity, and incomplete penetrance observed in this condition. Finally, this work demonstrates the value of sequencing-based GWAS methodology in rare disease, beyond conventional monogenic gene discovery, and provides strong support for an inclusive diverse-ancestry approach