Abstract: Nephrotic syndrome (NS) is the second most common cause of end-stage kidney disease (ESKD) before age twenty-five. The spectrum of disease is defined by response to steroids, divided into steroid resistant nephrotic syndrome (SRNS) and steroid sensitive nephrotic syndrome (SSNS). SRNS has limited therapeutic options and often progresses to chronic kidney disease (CKD) and ESKD, while SSNS carries significant morbidity due to long-term treatment with non-specific immunosuppression. We aim to improve our understanding of the genetic drivers of NS to more precisely guide clinical management and create targeted therapies. The past two decades have seen an increased understanding of the genetic basis of NS, particularly in the discovery of Mendelian causes of NS. Mendelian forms of NS are primarily recessive, with two pathogenic variants being essentially fully penetrant for the more severe form of NS, SRNS. The first recessive Mendelian NS gene discovered was nephrin (NPHS1). In keeping with this inheritance model, the heterozygous state has been thought to be clinically silent – a true “carrier” state. Recently, a published analysis of a Finnish population cohort (FinnGen) challenged that model by showing that carriers of “Fin-Major”, a specific NPHS1 loss-of- function Mendelian founder mutation in Finns, have increased odds of kidney disease. Additionally, genome wide association studies (GWAS) have implicated common variants in NPHS1 with increased risk of SSNS, reduced estimated glomerular filtration rate (eGFR), and lower serum albumin. Taken together, these discoveries suggest that forms of genetic variation beyond bi-allelic Mendelian variants, such as heterozygous rare pathogenic coding variants and common regulatory variants, may alter NPHS1 function and contribute to kidney dysfunction and disease. The overall goal of my project is to discover the association of coding and non-coding NPHS1 variants across the allele frequency spectrum with diverse kidney diseases and traits. More specifically, I hypothesize that in the general population, heterozygous, pathogenic Mendelian NPHS1 variants and common risk variants discovered by GWAS are associated with lower eGFR, higher urine protein levels, and increased odds of nephrotic syndrome. To test this hypothesis, I propose testing the following specific aims amongst 1.5 million people enrolled in multiple large population- and hospital system-based biorepositories: Aim 1: Discover the clinical consequences of Fin-Major carrier state in the FinnGen cohort. Aim 2: Discover the prevalence and clinical impact of rare and common NPHS1 variants in 5 hospital based and population cohorts collectively totaling approximately 1,500,000 individuals.

Narrative Nephrotic syndrome (NS), a rare kidney disease that nevertheless is the second leading cause of end stage renal disease in patients under 25. Rare loss of function variants within NPHS1, which encodes the protein nephrin, critical to maintenance of the slit diaphragm of the glomerulus, are known to cause severe forms of NS with recessive inheritance. This study will discover the clinical consequences of NPHS1 variants across the allele frequency spectrum by studying the association of heterozygous rare pathogenic coding variants and common non-coding variants with kidney disease states and quantitative phenotypes of kidney dysfunction.