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Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

Original publication

DOI

10.1016/j.kint.2022.05.021

Type

Journal article

Journal

Kidney international

Publication Date

09/2022

Volume

102

Pages

624 - 639

Addresses

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany; Department of Nephrology, University Hospital Regensburg, Regensburg, Germany. Electronic address: mathias.gorski@klinik.uni-regensburg.de.

Keywords

Lifelines Cohort Study, Kidney, Humans, N-Acetylgalactosaminyltransferases, Glomerular Filtration Rate, Longitudinal Studies, Cross-Sectional Studies, Renal Insufficiency, Chronic, Renal Insufficiency, Genome-Wide Association Study, Genetic Loci