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

TitleTrans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.
Publication TypeJournal Article
Year of Publication2019
AuthorsMorris AP, Le TH, Wu H, Akbarov A, van der Most PJ, Hemani G, Smith G D, Mahajan A, Gaulton KJ, Nadkarni GN, Valladares-Salgado A, Wacher-Rodarte N, Mychaleckyj JC, Dueker ND, Guo X, Hai Y, Haessler J, Kamatani Y, Stilp AM, Zhu G, Cook JP, rnlöv JÄ, Blanton SH, de Borst MH, Bottinger EP, Buchanan TA, Cechova S, Charchar FJ, Chu P-L, Damman J, Eales J, Gharavi AG, Giedraitis V, Heath AC, Ipp E, Kiryluk K, Kramer HJ, Kubo M, Larsson A, Lindgren CM, Lu Y, Madden PAF, Montgomery GW, Papanicolaou GJ, Raffel LJ, Sacco RL, Sanchez E, Stark H, Sundström J, Taylor KD, Xiang AH, Zivkovic A, Lind L, Ingelsson E, Martin NG, Whitfield JB, Cai J, Laurie CC, Okada Y, Matsuda K, Kooperberg C, Chen Y-D I, Rundek T, Rich SS, Loos RJF, Parra EJ, Cruz M, Rotter JI, Snieder H, Tomaszewski M, Humphreys BD
Secondary AuthorsFranceschini N
JournalNat Commun
Volume10
Issue1
Pagination29
Date Published2019 01 03
ISSN2041-1723
KeywordsAdult, Aged, Blood Pressure, Ethnic Groups, Female, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Histone Code, Histones, Humans, Hypertension, Kidney, Kidney Calculi, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic
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.

DOI10.1038/s41467-018-07867-7
Alternate JournalNat Commun
PubMed ID30604766
PubMed Central IDPMC6318312
Grant ListP50 HD028138 / HD / NICHD NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R01 DK105124 / DK / NIDDK NIH HHS / United States
MC_UU_00011/1 / MRC_ / Medical Research Council / United Kingdom
PG/17/35/33001 / BHF_ / British Heart Foundation / United Kingdom
R37 NS029993 / NS / NINDS NIH HHS / United States
R21 HL123677 / HL / NHLBI NIH HHS / United States
R01 DK113632 / DK / NIDDK NIH HHS / United States
P30 DK116074 / DK / NIDDK NIH HHS / United States
R21 HL140385 / HL / NHLBI NIH HHS / United States
UL1 TR002736 / TR / NCATS NIH HHS / United States
R56 DK104806 / DK / NIDDK NIH HHS / United States
R01 DK117445 / DK / NIDDK NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
S10 OD020069 / OD / NIH HHS / United States
R01 MD012765 / MD / NIMHD NIH HHS / United States