Genetic Insight into Primary Glomerulonephritis
Primary glomerulonephritis is a major global health concern and a disorder with significant heritable components. Rapid advances in sequencing technologies have led to genome-wide, high-throughput investigations of the genetic basis of complex human traits. Genetic studies have successfully mapped several susceptibility loci and disease-causing genes for different subtypes of primary glomerulonephritis. These studies have revealed that IgA nephropathy–associated genes have a highly complex, polygenic, and pleiotropic genetic architecture and that genetic susceptibility to membranous nephropathy may be driven by a few large-effect loci. Furthermore, both susceptibility genes and high-penetrant gene mutations reportedly contribute to the development of the most heterogeneous phenotype of focal segmental glomerulosclerosis. The genetic heterogeneity between each glomerular disease type and within different populations have indicated disease-specific and ethnicity-specific underlying molecular mechanisms for the disorders. Findings from genome-wide association studies (GWAS) have mainly included variants on or near the major histocompatibility (MHC) loci, highlighting the molecular basis for the shared pathogenesis of the immune-mediated disease. Recent studies with increased sample sizes and higher resolutions of genome-wide imputation have provided novel insights into the pathogenesis of glomerular disorders. Further integration of results from genomic studies with functional genomics datasets can indicate novel targets for drug discovery as well as potential tools for patient diagnosis and stratification. However, larger GWASs and sequencing studies in independent cohorts and more standardised inclusion of phenotypes across studies are required for each subtype of glomerular disease.