Defining Causal Variants and Associated Genes in Polygenic Nephrolithiasis

Kidney stones, which are a major clinical and economic health burden, are commonly recurrent, and current stone prevention strategies are relatively ineffective.

The renal tubular mechanisms underlying this disease are poorly understood, thereby limiting opportunities to develop novel therapies. Via a genome-wide association study (GWAS) we identified twenty genetic loci linked to kidney stone formation. However, the genes influenced by these loci remain to be elucidated.

My goals are to: identify additional stone-associated loci by X chromosome and sex-specific GWAS studies; define biologically relevant renal cell types by identifying areas of accessible chromatin at relevant loci through single cell assays for transposase accessible chromatin (ATAC)-sequencing in renal tissue; determine causal GWAS-associated SNPs by examining local epigenetic modifications in relevant cell types via chromatin immunoprecipitation (ChIP)-sequencing; link causal SNPs to effector genes by determining the 3-dimensional chromatin landscape in relevant cell types through Next Generation Chromatin Conformation Capture; validate predicted genotype-phenotype associations in relevant cohorts; and elucidate the roles of effector genes in cellular function via in vitro studies.

This research will provide new insights into tubular function and the molecular pathophysiology of renal stone disease and reveal new therapeutic targets for the prevention of kidney stone recurrence.