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

Teumer A, Li Y, Ghasemi S, Prins BP, Wuttke M, Hermle T, Giri A, Sieber KB, Qiu C, Kirsten H, Tin A, Chu AY, Bansal N, Feitosa MF, Wang L, Chai JF, Cocca M, Fuchsberger C, Gorski M, Hoppmann A, Horn K, Li M, Marten J, Noce D, Nutile T, Sedaghat S, Sveinbjornsson G, Tayo BO, van der Most PJ, Xu Y, Yu Z, Gerstner L, Ärnlöv J, Bakker SJ, Baptista D, Biggs ML, Boerwinkle E, Brenner H, Burkhardt R, Carroll RJ, Chee ML, Chee ML, Chen M, Cheng CY, Cook JP, Coresh J, Corre T, Danesh J, de Borst MH, De Grandi A, de Mutsert R, de Vries AP, Degenhardt F, Dittrich K, Divers J, Eckardt KU, Ehret G, Endlich K, Felix JF, Franco OH, Franke A, Freedman BI, Freitag-Wolf S, Gansevoort RT, Giedraitis V, Gögele M, Grundner-Culemann F, Gudbjartsson DF, Gudnason V, Hamet P, Harris TB, Hicks AA, Holm H, Foo VHX, Hwang SJ, Ikram MA, Ingelsson E, Jaddoe VW, Jakobsdottir J, Josyula NS, Jung B, Kähönen M, Khor CC, Kiess W, Koenig W, Körner A, Kovacs P, Kramer H, Krämer BK, Kronenberg F, Lange LA, Langefeld CD, Lee JJM, Lehtimäki T, Lieb W, Lim SC, Lind L, Lindgren CM, Liu J, Loeffler M, Lyytikäinen LP, Mahajan A, Maranville JC, Mascalzoni D, McMullen B, Meisinger C, Meitinger T, Miliku K, Mook-Kanamori DO, Müller-Nurasyid M, Mychaleckyj JC, Nauck M, Nikus K, Ning B, Noordam R, Connell JO, Olafsson I, Palmer ND, Peters A, Podgornaia AI, Ponte B, Poulain T, Pramstaller PP, Rabelink TJ, Raffield LM, Reilly DF, Rettig R, Rheinberger M, Rice KM, Rivadeneira F, Runz H, Ryan KA, Sabanayagam C, Saum KU, Schöttker B, Shaffer CM, Shi Y, Smith AV, Strauch K, Stumvoll M, Sun BB, Szymczak S, Tai ES, Tan NY, Taylor KD, Teren A, Tham YC, Thiery J, Thio CH, Thomsen H, Thorsteinsdottir U, Tönjes A, Tremblay J, Uitterlinden AG, van der Harst P, Verweij N, Vogelezang S, Völker U, Waldenberger M, Wang C, Wilson OD, Wong C, Wong TY, Yang Q, Yasuda M, Akilesh S, Bochud M, Böger CA, Devuyst O, Edwards TL, Ho K, Morris AP, Parsa A, Pendergrass SA, Psaty BM, Rotter JI, Stefansson K, Wilson JG, Susztak K, Snieder H, Heid IM, Scholz M, Butterworth AS, Hung AM, Pattaro C, Köttgen A (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 10

Pages Range: 4130-

Journal Issue: 1

DOI: 10.1038/s41467-019-11576-0

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.

Authors with CRIS profile

Involved external institutions

GlaxoSmithKline Research and Development United States (USA) (US) Universität Leipzig Germany (DE) Albert-Ludwigs-Universität Freiburg Germany (DE) eurac research Italy (IT) Icelandic Heart Association (IHA) Iceland (IS) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Wake Forest School of Medicine United States (USA) (US) Erasmus University Medical Center (MC) Netherlands (NL) Tampere University Hospital / Tampereen yliopistollinen sairaala (TAYS) Finland (FI) Christian-Albrechts-Universität zu Kiel Germany (DE) Leiden University Medical Center Netherlands (NL) University of Cambridge United Kingdom (GB) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Uppsala University Sweden (SE) National University of Singapore (NUS) Singapore (SG) Merck & Co., Inc. / Merck Sharp & Dohme Corp (MSD) United States (USA) (US) Vanderbilt University Medical Center United States (USA) (US) deCODE genetics Iceland (IS) Landspítali / National University Hospital of Iceland Iceland (IS) Boston University United States (USA) (US) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) University of Virginia (UVA) United States (USA) (US) Centre hospitalier de l'Université de Montréal (CHUM) Canada (CA) Johns Hopkins University (JHU) United States (USA) (US) University of Utah United States (USA) (US) Universitätsklinikum Regensburg Germany (DE) Stanford University United States (USA) (US) Deutsches Herzzentrum München Germany (DE) Washington University in St. Louis United States (USA) (US) Framingham Heart Study United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Geisinger Health System United States (USA) (US) Institute of genetics and biophysics "Adriano Buzzati Traverso" (IGB) Italy (IT) Universitätsklinikum Mannheim Germany (DE) Vanderbilt University United States (USA) (US) University of Washington United States (USA) (US) Loyola University Chicago United States (USA) (US) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) The University of Liverpool United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Karolinska Institute Sweden (SE) National University Health System (NUHS) Singapore (SG) Fimlab Laboratories Finland (FI) Genome Institute of Singapore Singapore (SG) University of Oxford United Kingdom (GB) Harbor–UCLA Medical Center United States (USA) (US) Université de Lausanne (UNIL) Switzerland (CH) University of Mississippi (Ole Miss) United States (USA) (US) University of Iceland (UI) / Háskóli Íslands Iceland (IS) University of Pennsylvania United States (USA) (US) University of North Carolina at Chapel Hill United States (USA) (US) NUS Yong Loo Lin School of Medicine Singapore (SG) Universitätsspital Zürich (USZ) Switzerland (CH) University of Maryland School of Pharmacy United States (USA) (US) Wellcome Centre for Human Genetics United Kingdom (GB) Universität Regensburg Germany (DE) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK / NIDDKD) United States (USA) (US) Medizinische Universität Innsbruck Austria (AT) MRC Institute of Genetics & Molecular Medicine MRC Human Genetics Unit United Kingdom (GB) I.R.C.C.S. materno infantile Burlo Garofolo Italy (IT) National Institute on Aging (NIA) United States (USA) (US) Division of Biomedical Informatics & Personalized Medicine United States (USA) (US)

How to cite

APA:

Teumer, A., Li, Y., Ghasemi, S., Prins, B.P., Wuttke, M., Hermle, T.,... Köttgen, A. (2019). Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nature Communications, 10(1), 4130-. https://doi.org/10.1038/s41467-019-11576-0

MLA:

Teumer, Alexander, et al. "Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria." Nature Communications 10.1 (2019): 4130-.

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