Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies

Andrew P. Morris, Thu H. Le, Haojia Wu, Artur Akbarov, Peter J. van der Most, Gibran Hemani, George Davey Smith, Anubha Mahajan, Kyle J. Gaulton, Girish N. Nadkarni, Adan Valladares-Salgado, Niels Wacher-Rodarte, Josyf C. Mychaleckyj, Nicole D. Dueker, Xiuqing Guo, Yang Hai, Jeffrey Haessler, Yoichiro Kamatani, Adrienne M. Stilp, Gu ZhuJames P. Cook, Johan Ärnlöv, Susan H. Blanton, Martin H. de Borst, Erwin P. Bottinger, Thomas A. Buchanan, Sylvia Cechova, Fadi J. Charchar, Pei Lun Chu, Jeffrey Damman, James Eales, Ali G. Gharavi, Vilmantas Giedraitis, Andrew C. Heath, Eli Ipp, Krzysztof Kiryluk, Holly J. Kramer, Michiaki Kubo, Anders Larsson, Cecilia M. Lindgren, Yingchang Lu, Pamela A.F. Madden, Grant W. Montgomery, George J. Papanicolaou, Leslie J. Raffel, Ralph L. Sacco, Elena Sanchez, Holger Stark, Johan Sundstrom, Kent D. Taylor, Anny H. Xiang, Aleksandra Zivkovic, Lars Lind, Erik Ingelsson, Nicholas G. Martin, John B. Whitfield, Jianwen Cai, Cathy C. Laurie, Yukinori Okada, Koichi Matsuda, Charles Kooperberg, Yii Der Ida Chen, Tatjana Rundek, Stephen S. Rich, Ruth J.F. Loos, Esteban J. Parra, Miguel Cruz, Jerome I. Rotter, Harold Snieder, Maciej Tomaszewski, Benjamin D. Humphreys, Nora Franceschini

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

Original languageEnglish (US)
Article number29
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Morris, A. P., Le, T. H., Wu, H., Akbarov, A., van der Most, P. J., Hemani, G., Smith, G. D., Mahajan, A., Gaulton, K. J., Nadkarni, G. N., Valladares-Salgado, A., Wacher-Rodarte, N., Mychaleckyj, J. C., Dueker, N. D., Guo, X., Hai, Y., Haessler, J., Kamatani, Y., Stilp, A. M., ... Franceschini, N. (2019). Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies. Nature communications, 10(1), [29]. https://doi.org/10.1038/s41467-018-07867-7