TY - JOUR
T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals
AU - Lifelines Cohort Study
AU - V. A. 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 - Campbell, Harry
N1 - Funding Information:
is supported by a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH) and consults for Illumina, the Michael J. Fox Foundation and University of California Healthcare. O.H.F. works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec); Metagenics; and AXA. K.B.S., L.Y.-A., D.M.W. and M.A.L. are full-time employees of GlaxoSmithKline. M.L.O’D. received grant support from GlaxoSmithKline, MSD, Eisai, AstraZeneca, MedCo and Janssen. H.W. received grants and non-financial support from GlaxoSmithKline, during the conduct of the study; grants from Sanofi-Aventis, Eli Lilly, the National Institute of Health, Omthera Pharmaceuticals, Pfizer New Zealand, Elsai Inc. and Dalcor Pharma UK; honoraria and non-financial support from AstraZeneca; and is on advisory boards for Sirtex and Acetilion and received personal fees from CSL Behring and American Regent outside the scope of the submitted work. L. Wallentin received institutional grants from GlaxoSmithKline, AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, MSD and Roche Diagnostics. D.F.R. and A.I.P. are employees of MSD. M. Scholz received consultancy of and grant support from Merck Serono not related to this project. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. J. Danesh is a member of the Novartis Cardiovascular and Metabolic Advisory Board and received grant support from Novartis. A.S.B. received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a honorarium from the same source for participating in an advisory board meeting. A. Köttgen received grant support from Gruenenthal. All other authors declare no conflicts of interest.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/6/1
Y1 - 2019/6/1
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.
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U2 - 10.1038/s41588-019-0407-x
DO - 10.1038/s41588-019-0407-x
M3 - Article
C2 - 31152163
AN - SCOPUS:85066607502
SN - 1061-4036
VL - 51
SP - 957
EP - 972
JO - Nature genetics
JF - Nature genetics
IS - 6
ER -
