Title | A catalog of genetic loci associated with kidney function from analyses of a million individuals. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Wuttke M, Li Y, Li M, et al. |
Secondary Authors | Pattaro C |
Corporate Authors | LifeLines Cohort Study, V. A. Million Veteran Program |
Journal | Nat Genet |
Volume | 51 |
Issue | 6 |
Pagination | 957-972 |
Date Published | 2019 06 |
ISSN | 1546-1718 |
Keywords | Chromosome 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. |
DOI | 10.1038/s41588-019-0407-x |
Alternate Journal | Nat Genet |
PubMed ID | 31152163 |
PubMed Central ID | PMC6698888 |
Grant List | RG/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 |