Multispecies, Integrative GWAS for Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a disease affecting the filtering unit of the kidney, the glomerulus, which is characterized by high morbidity, poor response to medical therapy, and high rate of progression to end-stage renal disease (ESRD) requiring dialysis or transplantation. Individuals of African ancestry have a four-fold increased risk of FSGS compared to Asians or Caucasians, suggesting a strong genetic contribution. Familial forms of disease account for a small proportion of cases with FSGS, and genetic variants in the gene called APOL1 do not fully explain the racial disparities in disease risk. These data suggest that other, yet unknown, common and rare genetic factors are also contributing to individuals of both African and non-African descent.

Genetic studies for human FSGS have traditionally explored only one genetic model at a time, either rare mutations responsible for rare or familial forms of disease or common genetic variants, but no study has approached this disease in a comprehensive fashion using both human genetics and mouse studies.

This proposal has its foundation on very large cohort patients (over 7,500), on a multidisciplinary team that showed collaboration and productivity over the past 10 years in identifying genetic variations underlying different forms of kidney diseases in human and mouse, and on novel but mature genomics approaches.

In this proposal, we formulate the original hypothesis that combined genetic studies across two different species, human and mouse, will augment analytic power and will shed light on the pathogenesis of FSGS. We will leverage a uniquely large cohort of patients with FSGS, substantial prior work for identifying susceptibility genes to FSGS in mice, and state-of-the-art analytical tools to solve the genetic determinants of FSGS.

Here we will interrogate both common and rare genetic variants in humans and mouse and generate new datasets, which in combination with our own gene expression datasets and public resources, are poised to identify underlying genetic mutations. To our knowledge, this will be the first comprehensive study using the genome-wide association design, bridging a significant knowledge gap in studies for this frequent cause of kidney failure.

In the short term, this study is designed to provide insight in the genetic causes of FSGS by identifying novel genes causally related to disease. In the long term, we anticipate developing new mouse models for FSGS and cellular systems in order to devise new targeted therapies that will impact and benefit treatment for chronic kidney disease at large in the general population as well as in the active duty personnel, Veterans, and their families.