TY - JOUR

T1 - Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies

AU - Gorski, Mathias

AU - Rasheed, Humaira

AU - Teumer, Alexander

AU - Thomas, Laurent F.

AU - Graham, Sarah E

AU - Sveinbjornsson, Gardar

AU - Winkler, Thomas W.

AU - Günther, Felix

AU - Stark, Klaus J.

AU - Chai, Jin-Fang

AU - Tayo, Bamidele O

AU - Wuttke, Matthias

AU - Li, Yong

AU - Tin, Adrienne

AU - Ahluwalia, Tarunveer S.

AU - Ärnlöv, Johan

AU - Åsvold, Bjørn Olav

AU - Bakker, Stephan J. L.

AU - Banas, Bernhard

AU - Bansal, Nisha

AU - Biggs, Mary L

AU - Biino, Ginevra

AU - Böhnke, Michael

AU - Boerwinkle, Eric

AU - Bottinger, Erwin P

AU - Brenner, Hermann

AU - Brumpton, Ben

AU - Carroll, Robert J

AU - Chaker, Layal

AU - Chalmers, John

AU - Chee, Miao-Li

AU - Chee, Miao-Ling

AU - Cheng, Ching-Yu

AU - Chu, Audrey Y

AU - Ciullo, Marina

AU - Cocca, Massimiliano

AU - Cook, James P

AU - Coresh, Josef

AU - Cusi, Daniele

AU - de Borst, Martin H

AU - Degenhardt, Frauke

AU - Eckardt, Kai-Uwe

AU - Endlich, Karlhans

AU - Evans, Michele K

AU - Feitosa, Mary F.

AU - Franke, Andre

AU - Freitag-Wolf, Sandra

AU - Rossing, Peter

AU - LifeLines Cohort Study

N1 - Publisher Copyright: © 2022 International Society of Nephrology

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - acute kidney injury

KW - chronic kidney disease

KW - diabetes

KW - gene expression

U2 - 10.1016/j.kint.2022.05.021

DO - 10.1016/j.kint.2022.05.021

M3 - Journal article

C2 - 35716955

AN - SCOPUS:85134811540

VL - 102

SP - 624

EP - 639

JO - Kidney International. Supplement

JF - Kidney International. Supplement

SN - 0098-6577

IS - 3

ER -