A catalog of genetic loci associated with kidney function from analyses of a million individuals

TY - JOUR

T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals

AU - LifeLines Cohort Study

AU - Million Veteran Program

AU - Wuttke, Matthias

AU - Li, Yong

AU - Li, Man

AU - Sieber, Karsten B.

AU - Feitosa, Mary F.

AU - Gorski, Mathias

AU - Tin, Adrienne

AU - Wang, Lihua

AU - Chu, Audrey Y.

AU - Hoppmann, Anselm

AU - Kirsten, Holger

AU - Giri, Ayush

AU - Chai, Jin-Fang

AU - Sveinbjornsson, Gardar

AU - Tayo, Bamidele O.

AU - Nutile, Teresa

AU - Fuchsberger, Christian

AU - Marten, Jonathan

AU - Cocca, Massimiliano

AU - Ghasemi, Sahar

AU - Xu, Yizhe

AU - Horn, Katrin

AU - Noce, Damia

AU - van der Most, Peter J.

AU - Sedaghat, Sanaz

AU - Yu, Zhi

AU - Akiyama, Masato

AU - Afaq, Saima

AU - Ahluwalia, Tarunveer S.

AU - Almgren, Peter

AU - Amin, Najaf

AU - Ärnlöv, Johan

AU - Bakker, Stephan J. L.

AU - Bansal, Nisha

AU - Baptista, Daniela

AU - Bergmann, Sven

AU - Biggs, Mary L.

AU - Biino, Ginevra

AU - Boehnke, Michael

AU - Boerwinkle, Eric

AU - Boissel, Mathilde

AU - Bottinger, Erwin P.

AU - Boutin, Thibaud S.

AU - Brenner, Hermann

AU - Brumat, Marco

AU - Burkhardt, Ralph

AU - Butterworth, Adam S.

AU - Campana, Eric

AU - Campbell, Archie

AU - Smith, Blair H.

AU - Köttgen, Anna

AU - Pattaro, Cristian

PY - 2019/6

Y1 - 2019/6

N2 - Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

AB - Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

UR - https://www.scopus.com/pages/publications/85066607502

U2 - 10.1038/s41588-019-0407-x

DO - 10.1038/s41588-019-0407-x

M3 - Article

C2 - 31152163

SN - 1061-4036

VL - 51

SP - 957

EP - 972

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -