Multiethnic Integrated GWAS to Illuminate the Pathobiology of FSGS

The Topic Area of our research program is Focal Segmental Glomerulosclerosis (FSGS), a form of nephrotic syndrome (NS) and a type of chronic kidney disease (CKD). FSGS occurs as a result of damage and scarring to the filtering units of the kidney, called glomeruli. This damage leads to massive urine loss of proteins, including infection-fighting antibodies, proteins that help the blood clotting system work appropriately, and proteins that keep fluids in blood vessels and not the tissues. These losses make patients with FSGS have increased risk of life-threatening bloodstream infections, blood clots, and painful swelling in the face, abdomen, and legs. Unfortunately, a large percentage of FSGS patients have progressive loss of kidney function. Many end up with end-stage kidney disease (ESKD), meaning that they need dialysis or a kidney transplant to survive. The most frustrating aspect of FSGS is that we do not have therapies specifically targeted against FSGS, which could treat, cure, or prevent it. Instead we rely on immunosuppressant medications, usually taken from the cancer field, and we then hope that our patients obtain remission of FSGS without being harmed by the side effects of these non-specific medications. We also don't have biomarkers to help doctors provide more accurate prognoses and more effective clinical care. This lack of targeted therapies and accurate biomarkers is largely due to the fact that FSGS is simply a descriptive classification based on findings from kidney tissue analysis at the microscope, representing the final common pathway of a heterogeneous group of kidney diseases. We cannot provide precision care directed against a disease characterized descriptively like this. We need to dissect the molecular anatomy of FSGS if we are going to discover targeted and more effective treatments/cures for our affected patients. In doing so, we also may be able to discover preventive measures that could prevent the development of FSGS in certain high-risk individuals. Our team believes that human genomic discovery is the most effective strategy to achieve this goal. Over the past decades, the discoveries of the genetic underpinning of FSGS have begun to illuminate its biology, identify molecular pathways that may be amendable for drug targeting, and allow creation of a genomic classification with clinically meaningful correlates. Nevertheless, most studies have analyzed small cohorts of patients and, notably, the role of common variants that might predispose to non-familial forms of disease, is virtually unknown. To address this, we propose to study the largest-ever assembled cohort of FSGS cases (over 12,000 cases) and integrate the results with genetic and expression studies in different mouse models of disease. To make these discoveries, we will perform state-of-the-art genomics studies in three distinct, but synergistic aims. In Aim 1, we will discover and validate new FSGS susceptibility genes by conducting the largest human genome-wide association study (GWAS) conducted so far for this disease. In Aim 2, we will conduct fine mapping and multi-omics studies to functionally annotate and investigate the loci and genes identified in Aim 1 and conduct novel analyses for genetic interactions and polygenic risk scores. In Aim 3, we will conduct gene expression studies using RNA sequencing methodologies from kidney tissues derived from three established mouse models of FSGS, from a new mouse model generated based on discoveries made with the previous cycle of funding, as well as from FSGS, patient-derived tissue: (a) the Actn4 knock-out and knock-in mouse (as a model of adult-onset FSGS); (b) the Nphs2 knock-out mouse (as a model of pediatric FSGS); (c) the HIV transgenic mouse (as a model of immune-mediate FSGS); (d) the Trim8 conditional knock-in mouse model carrying the human p.Q459* mutations; and (d) glomerular transcriptomic profiles derived from kidney biopsies of FSGS patients. These studies wi