Pulse lineResearch With Heart Logo

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

TitleA catalog of genetic loci associated with kidney function from analyses of a million individuals.
Publication TypeJournal Article
Year of Publication2019
AuthorsWuttke M, Li Y, Li M, et al.
Secondary AuthorsPattaro C
Corporate AuthorsLifeLines Cohort Study, V. A. Million Veteran Program
JournalNat Genet
Volume51
Issue6
Pagination957-972
Date Published2019 06
ISSN1546-1718
KeywordsChromosome Mapping, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inheritance Patterns, Kidney Function Tests, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Renal Insufficiency, Chronic, Uromodulin
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.

DOI10.1038/s41588-019-0407-x
Alternate JournalNat Genet
PubMed ID31152163
PubMed Central IDPMC6698888
Grant ListRG/18/13/33946 / BHF_ / British Heart Foundation / United Kingdom
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
R01 DK062370 / DK / NIDDK NIH HHS / United States
T32 HL129982 / HL / NHLBI NIH HHS / United States
S10 OD023680 / OD / NIH HHS / United States
MR/R023484/1 / MRC_ / Medical Research Council / United Kingdom
U01 AG023746 / AG / NIA NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
P30 DK116074 / DK / NIDDK NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
Z01 AG000513-08 / ImNIH / Intramural NIH HHS / United States
R01 DK093757 / DK / NIDDK NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
Z99 AG999999 / ImNIH / Intramural NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 HL088215 / HL / NHLBI NIH HHS / United States
K12 HD043483 / HD / NICHD NIH HHS / United States