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 J-F., 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 SJL., Baptista D., Biggs ML., Boerwinkle E., Brenner H., Burkhardt R., Carroll RJ., Chee M-L., Chee M-L., Chen M., Cheng C-Y., Cook JP., Coresh J., Corre T., Danesh J., de Borst MH., De Grandi A., de Mutsert R., de Vries APJ., Degenhardt F., Dittrich K., Divers J., Eckardt K-U., 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 S-J., Ikram MA., Ingelsson E., Jaddoe VWV., Jakobsdottir J., Josyula NS., Jung B., Kähönen M., Khor C-C., Kiess W., Koenig W., Körner A., Kovacs P., Kramer H., Krämer BK., Kronenberg F., Lange LA., Langefeld CD., Lee JJ-M., Lehtimäki T., Lieb W., Lim S-C., Lind L., Lindgren CM., Liu J., Loeffler M., Lyytikäinen L-P., 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 K-U., Schöttker B., Shaffer CM., Shi Y., Smith AV., Strauch K., Stumvoll M., Sun BB., Szymczak S., Tai E-S., Tan NYQ., Taylor KD., Teren A., Tham Y-C., Thiery J., Thio CHL., 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 T-Y., 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.
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.