Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies

• Verfasst von: Gorski, Mathias [VerfasserIn]
• Verfasst von: Brenner, Hermann [VerfasserIn]
• Verfasst von: Holleczek, Bernd [VerfasserIn]
• Verfasst von: Krämer, Bernhard [VerfasserIn]
• Verfasst von: Schöttker, Ben [VerfasserIn]
• Verfasst von: Stocker, Hannah [VerfasserIn]
• Titel: Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
• Verf.angabe: Mathias Gorski, Hermann Brenner, Bernd Holleczek, Bernhard K. Krämer, Ben Schöttker, Hannah Stocker [und viele weitere]
• E-Jahr: 2022
• Jahr: 16 June 2022
• Umfang: 16 S.
• Fussnoten: Gesehen am 26.01.2023
• Titel Quelle: Enthalten in: Kidney international
• Ort Quelle: New York, NY : Elsevier, 1972
• Jahr Quelle: 2022
• Band/Heft Quelle: 102(2022), 3 vom: Sept., Seite 624-639
• ISSN Quelle: 1523-1755
• DOI: doi:10.1016/j.kint.2022.05.021
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: acute kidney injury
• Sach-SW: chronic kidney disease
• Sach-SW: diabetes
• Sach-SW: gene expression
• K10plus-PPN: 1832479633

Abstract

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.