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

Teumer, Alexander; Li, Yong; Ghasemi, Sahar; Prins, Bram P; Wuttke, Matthias; Hermle, Tobias; Giri, Ayush; Sieber, Karsten B; Qiu, Chengxiang; Kirsten, Holger; Tin, Adrienne; Chu, Audrey Y; Bansal, Nisha; Feitosa, Mary F; Wang, Lihua; Chai, Jin-Fang; Cocca, Massimiliano; Fuchsberger, Christian; Gorski, Mathias; Hoppmann, Anselm; ... (2019). Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nature communications, 10(1), p. 4130. Nature Publishing Group 10.1038/s41467-019-11576-0

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine

UniBE Contributor:

Franco Duran, Oscar Horacio

Subjects:

600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Beatrice Minder Wyssmann

Date Deposited:

18 Sep 2019 16:26

Last Modified:

22 Oct 2019 16:43

Publisher DOI:

10.1038/s41467-019-11576-0

PubMed ID:

31511532

BORIS DOI:

10.7892/boris.133354

URI:

https://boris.unibe.ch/id/eprint/133354

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