Abstract: IgA Nephropathy is the most common form of primary glomerulonephritis and an important cause of kidney failure worldwide. The affected individuals develop characteristic IgA1-containing antibody complexes that deposit in the kidney, producing progressive renal injury. The disease is associated with a specific pathogenic defect in the O-glycosylation of IgA1 that promotes formation of immune complexes. Similar to other immune- mediated disorders, IgA nephropathy has a complex genetic architecture. In the prior funding period, we completed a GWAS for IgA nephropathy (10,146 cases and 28,751 controls) and we identified 30 genome- wide significant risk loci, explaining 11% of disease risk. We observed clear convergence of biological candidate genes on a common set of cytokine ligand-receptor pairs involved in mucosal IgA responses, including on targets of existing drugs. In a GWAS of 2,170 cases and 5,928 controls, we also defined novel genome-wide significant loci for IgA vasculitis, a related childhood condition with kidney complications. We further enhanced these efforts by studies of serum IgA (GWAS in 41,263 individuals) and galactose-deficient- IgA1 levels (GWAS in 10,193 individuals). Mendelian randomization provided strong genetic support for the causal role of these endophenotypes. The overall goal of this proposal is to leverage these findings to identify causal genes underlying shared genetic susceptibility between these traits. In Aim 1, we plan to conduct multi- phenotype mapping across all four traits to better define shared and trait-specific loci. Multiome single nuclei sequencing will be used to generate high resolution regulatory maps of IgA+ cells for fine-mapping and prioritization of candidate causal genes. In Aim 2, we will study the role of the prioritized genes in health and disease by leveraging Pakistani Genomic Resource, the largest cohort of human knockouts (KOs), with homozygous KOs for >5000 genes and heterozygous KOs for >18,000 genes. We will perform call-back studies in selected consanguineous families to identify carriers of loss-of-function and gain-of-function variants in the genes of interest, followed by clinical and detailed immunophenotyping studies. These efforts will be complemented by targeted gene perturbation experiments in IgA1-producing cells. In Aim 3, we will perform phenome-wide association studies, and correlate our new genetic findings with clinical features. Based on these findings, we will formulate and validate an integrated genomic risk score for kidney disease progression in two large prospective cohorts of IgA nephropathy and IgA vasculitis with nephritis. These studies are expected to refine our proposed disease pathogenesis model, define new therapeutic targets, and accelerate clinical translation of our genetic findings.