Genetic Determinants of IgA Nephropathy: Western Perspective

Abstract

IgA nephropathy (IgAN) represents a genetically complex multifactorial trait. Its prevalence and clinical features vary geographically, and the disease has a range of clinical presentations that suggest multiple subtypes. Although familial aggregation of IgAN has been reported and prior linkage studies have highlighted significant locus heterogeneity, specific genetic variants underlying familial IgAN have not yet been defined. Population-based genome-wide association studies (GWAS) have discovered nearly 20 IgAN risk loci, providing novel insights into disease epidemiology and molecular mechanisms, shifting old paradigms of the disease pathogenesis. Follow-up fine-mapping studies have identified specific causal variants, and genotype-phenotype correlation studies have begun to delineate clinical consequences of GWAS risk alleles. The association between IgAN and galactose-deficient IgA1 (Gd-IgA1), a validated serum biomarker of IgAN, presented another avenue for genetic discovery because elevated serum levels of Gd-IgA1 are highly heritable. Recent GWAS for serum Gd-IgA1 levels provided novel insights into genetic regulation of this trait, but the genetic link between Gd-IgA1 and IgAN has not yet been established. In this review, we discuss these developments in the broader context of modern genetic approaches to complex traits, and provide our perspective on the critical challenges that need to be addressed to advance the field.

Keywords: GWAS; IgA nephropathy; complex traits; exome sequencing; galactose-deficient IgA1; human genetics; linkage analysis; next-generation sequencing; whole genome sequencing.