Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

Kira J. Stanzick; Yong Li; Pascal Schlosser; Mathias Gorski; Matthias Wuttke; Laurent F. Thomas; Humaira Rasheed; Bryce X. Rowan; Sarah E. Graham; Brett R. Vanderweff; Snehal B. Patil; VA Million Veteran Program; Cassianne Robinson‐Cohen; J. Michael Gaziano; Christopher J. O’Donnell; Cristen J. Willer; Stein Ivar Hallan; Bjørn Olav Åsvold; André Gessner; Adriana M. Hung; Cristian Pattaro; Anna Köttgen; Klaus J. Stark; Iris M. Heid; Thomas W. Winkler

doi:10.1038/s41467-021-24491-0

GeneticsNature CommunicationsJul 16, 2021

Peer-reviewed journal article

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

Kira J. Stanzick iD, Yong Li iD, Pascal Schlosser iD, Mathias Gorski iD, Matthias Wuttke iD, Laurent F. Thomas iD, Humaira Rasheed iD, Bryce X. Rowan iD, Sarah E. Graham iD, Brett R. Vanderweff, Snehal B. Patil iD, VA Million Veteran Program, Cassianne Robinson‐Cohen iD, J. Michael Gaziano iD, Christopher J. O’Donnell iD, Cristen J. Willer iD, Stein Ivar Hallan iD, Bjørn Olav Åsvold iD, André Gessner, Adriana M. Hung iD, Cristian Pattaro iD, Anna Köttgen iD, Klaus J. Stark iD, Iris M. Heid iD, Thomas W. Winkler iD

Abstract

Chronic kidney disease (CKD) has a complex genetic underpinning. Genome-wide association studies (GWAS) of CKD-defining glomerular filtration rate (GFR) have identified hundreds of loci, but prioritization of variants and genes is challenging. To expand and refine GWAS discovery, we meta-analyzed GWAS data for creatinine-based estimated GFR (eGFRcrea) from the Chronic Kidney Disease Genetics Consortium (CKDGen, n=765,348, trans-ethnic) and UK Biobank (UKB, n=436,581, Europeans). The results (i) extend the number of eGFRcrea loci (424 loci; 201 novel; 8.9% eGFRcrea variance explained by 634 independent signals); (ii) improve fine-mapping resolution (138 99% credible sets with [≤]5 variants, 44 single-variant sets); (iii) ascertain likely kidney function relevance for 343 loci (consistent association with alternative biomarkers); and (iv) highlight 34 genes with strong evidence by a systematic Gene PrioritiSation (GPS). We provide a sortable, searchable and customizable GPS tool to navigate through the in silico functional evidence and select relevant targets for functional investigations.

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