Chronic Kidney Disease: Novel Insights from Genome-Wide Association Studies

Abstract

Chronic kidney disease (CKD) is common, affecting about 10% of the general population, and causing significant morbidity and mortality. Apart from the risk conferred by traditional cardiovascular risk factors, there is a strong genetic component. The method of a genome-wide association study (GWAS) is a powerful hypothesis-free approach to unravel this component by association analyses of CKD with several million genetic variants distributed across the genome. Since the publication of the first GWAS in 2005, this method has led to the discovery of novel loci for numerous human common diseases and phenotypes. Here, we review the recent successes of meta-analyses of GWAS on renal phenotypes. UMOD, SHROOM3, STC1, LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2/SH2B3, DACH1, UBE2Q2, and SLC7A9 were uncovered as loci associated with estimated glomerular filtration rate (eGFR) and CKD, and CUBN as a locus for albuminuria in cross-sectional data of general population studies. However, less than 1.5% of the total variance of eGFR and albuminuria is explained by the identified variants, and the relative risk for CKD is modified by at most 20% per locus. In African Americans, much of the risk for end-stage nondiabetic kidney disease is explained by common variants in the MYH9/APOL1 locus, and in individuals of European descent, variants in HLA-DQA1 and PLA₂R1 implicate most of the risk for idiopathic membranous nephropathy. In contrast, genetic findings in the analysis of diabetic nephropathy are inconsistent. Uncovering variants explaining more of the genetically determined variability of kidney function is hampered by the multifactorial nature of CKD and different mechanisms involved in progressive CKD stages, and by the challenges in elucidating the role of low-frequency variants. Meta-analyses with larger sample sizes and analyses of longitudinal renal phenotypes using higher-resolution genotyping data are required to uncover novel loci associated with severe renal phenotypes.

Mapping genetic determinants of kidney damage in rat models

“…99,188,189 So far susceptibility loci could be identified on all human chromosomes (HSA), 1-22, except the sex chromosomes. 2,3,8,99,188,[190][191][192][193][194][195][196][197][198][199][200][201] Only a few studies, however, were successful, identifying within their associated genomic interval a single locus with a plausible candidate as a susceptibility locus for more common forms of CKD. Thus, a locus on chromosome 22 carrying a variant in the Apolipoprotein L-1 (APOL1) gene has been shown to explain a major portion of the increased genetic risk for non-diabetic CKD observed in African Americans.…”

Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity

“…P1244L variant disrupted the function of human SHROOM3 gene GWAS have detected common noncoding variants in SHROOM3 that are significantly associated with CKD, but the overall contribution of these variants to CKD risk is modest (Boger and Heid 2011). To identify other potential contributors to the disease risk, we tested variants in the human SHROOM3 exon5, which harbors the ASD1 actin-binding domain, for association with nondiabetic end-stage kidney disease (ESKD) in 2465 African Americans.…”

Association of vitamin D receptor gene polymorphisms with end-stage renal disease and the development of high-turnover renal osteodystrophy in a Chinese population

“…End-stage renal disease (ESRD) is the partial or total loss of kidney function (Duseja et al, 2012). It is well recognized that CKD leading to ESRD is caused by complex pathogenic mechanisms that result from the interactions between multiple genes and environmental factors (Adler, 2006;Böger and Heid, 2011;Dwivedi et al, 2011). Due to the difficulty in stabilizing the disease, patients often develop various abnormalities in bone and mineral metabolism, which significantly increases morbidity and mortality (Erturk and DialGene Consortium, 2006).…”