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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

TitleGenome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.
Publication TypeJournal Article
Year of Publication2019
AuthorsTeumer A, Li Y, Ghasemi S, et al.
Secondary AuthorsKöttgen A
JournalNat Commun
Volume10
Issue1
Pagination4130
Date Published2019 09 11
ISSN2041-1723
KeywordsAlbuminuria, Animals, Chromosome Mapping, Creatinine, Diabetes Mellitus, Drosophila melanogaster, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Phenomics, Risk Factors
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

DOI10.1038/s41467-019-11576-0
Alternate JournalNat Commun
PubMed ID31511532
PubMed Central IDPMC6739370
Grant ListMC_QA137853 / MRC_ / Medical Research Council / United Kingdom
T32 HL129982 / HL / NHLBI NIH HHS / United States
K12 HD043483 / HD / NICHD NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
P30 DK116074 / DK / NIDDK NIH HHS / United States