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

Lifelines Cohort Study, V. A. Million Veteran Program

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)957-972
Number of pages16
JournalNature Genetics
Volume51
Issue number6
DOIs
StatePublished - Jun 1 2019

Bibliographical note

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.

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