GWAS-Based Discoveries in IgA Nephropathy, Membranous Nephropathy, and Steroid-Sensitive Nephrotic Syndrome
Year: 2020
Type: review
Abstract: Over the past decade, genome-wide association studies (GWAS) have emerged as a powerful tool to understand the genetic basis of complex traits in humans. The GWAS approach has been successfully applied to primary glomerular disorders, providing numerous novel insights into the genetic architecture of IgA nephropathy, membranous nephropathy, and steroid-sensitive nephrotic syndrome. IgA nephropathy appears to have a highly complex polygenic architecture, with nearly 20 genome-wide significant loci of small-to-moderate effects discovered to date. In contrast, the genetic susceptibility to membranous nephropathy and steroid-sensitive nephrotic syndrome appears to be driven by a small number of large-effect loci. The MHC locus on chromosome 6p21 is strongly associated with genetic susceptibility to all major types of immune-mediated glomerulopathies. However, a distinct set of classical HLA alleles is associated with each individual disease type, pinpointing to specific immune mechanisms underlying each of these conditions. Additional insights from the discovery of non-HLA risk loci reinforced the role of innate and adaptive immunity in the pathogenesis of these disorders, and highlighted important susceptibility overlaps between glomerular and other autoimmune and inflammatory conditions. Despite these initial successes, much larger GWAS and sequencing studies are still needed for each individual glomerular disease type. Increased power will be critical to comprehensively test for genetic effects across the full spectrum of allelic frequencies, to detect gene-gene and gene-environment interactions, and to potentially improve the performance of polygenic risk predictors. Moreover, the existing studies are limited mostly to European and East Asian populations, stressing the urgency to expand genetic discovery efforts to more diverse populations worldwide.
DOI: 10.2215/cjn.14031119
Institution: Columbia University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Genomics of glomerular disease, Kidney Precision Medicine Program (KPMP): Columbia AKI Recruitment Site, Kidney Precision Medicine Program (KPMP): Columbia AKI Recruitment Site, Genetics of IgA nephropathy by integrative network-based association studies, Training Medical Students in NIDDK Research
OpenAlex ID: W3043693295