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 Zhu; James 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

doi:10.1038/s41467-018-07867-7

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 journal › Article › peer-review

Abstract

© 2019, The Author(s). 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 language	English
Article number	29
Pages (from-to)	29
Journal	Nature Communications
Volume	10
Issue number	1
Early online date	3 Jan 2019
DOIs	https://doi.org/10.1038/s41467-018-07867-7
Publication status	Published - 1 Dec 2019

Keywords

Adult
Aged
Blood Pressure/genetics
Ethnic Groups/genetics
Female
Genetic Loci/genetics
Genome-Wide Association Study
Glomerular Filtration Rate/genetics
Histone Code/genetics
Histones/metabolism
Humans
Hypertension/ethnology
Kidney Calculi/ethnology
Kidney/physiopathology
Male
Middle Aged
Polymorphism, Single Nucleotide
Renal Insufficiency, Chronic/ethnology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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http://www.nature.com/articles/s41467-018-07867-7

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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. Article 29. https://doi.org/10.1038/s41467-018-07867-7

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

abstract = "{\textcopyright} 2019, The Author(s). 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.",

keywords = "Adult, Aged, Blood Pressure/genetics, Ethnic Groups/genetics, Female, Genetic Loci/genetics, Genome-Wide Association Study, Glomerular Filtration Rate/genetics, Histone Code/genetics, Histones/metabolism, Humans, Hypertension/ethnology, Kidney Calculi/ethnology, Kidney/physiopathology, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic/ethnology",

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

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Morris, AP, Le, TH, Wu, H, Akbarov, A, Van Der Most, PJ, Hemani, G, Smith, GD, 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, Ärnlöv, J, Blanton, SH, De Borst, MH, Bottinger, EP, Buchanan, TA, Cechova, S, Charchar, FJ, Chu, P, 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, Sundstrom, 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, YI, Rundek, T, Rich, SS, Loos, RJF, Parra, EJ, Cruz, M, Rotter, JI, Snieder, H, Tomaszewski, M, Humphreys, BD & Franceschini, N 2019, 'Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies', Nature Communications, vol. 10, no. 1, 29, pp. 29. https://doi.org/10.1038/s41467-018-07867-7

TY - JOUR

T1 - Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies

AU - Morris, Andrew P.

AU - Le, Thu H.

AU - Wu, Haojia

AU - Akbarov, Artur

AU - Van Der Most, Peter J.

AU - Hemani, Gibran

AU - Smith, George Davey

AU - Mahajan, Anubha

AU - Gaulton, Kyle J.

AU - Nadkarni, Girish N.

AU - Valladares-salgado, Adan

AU - Wacher-rodarte, Niels

AU - Mychaleckyj, Josyf C.

AU - Dueker, Nicole D.

AU - Guo, Xiuqing

AU - Hai, Yang

AU - Haessler, Jeffrey

AU - Kamatani, Yoichiro

AU - Stilp, Adrienne M.

AU - Zhu, Gu

AU - Cook, James P.

AU - Ärnlöv, Johan

AU - Blanton, Susan H.

AU - De Borst, Martin H.

AU - Bottinger, Erwin P.

AU - Buchanan, Thomas A.

AU - Cechova, Sylvia

AU - Charchar, Fadi J.

AU - Chu, Pei-lun

AU - Damman, Jeffrey

AU - Eales, James

AU - Gharavi, Ali G.

AU - Giedraitis, Vilmantas

AU - Heath, Andrew C.

AU - Ipp, Eli

AU - Kiryluk, Krzysztof

AU - Kramer, Holly J.

AU - Kubo, Michiaki

AU - Larsson, Anders

AU - Lindgren, Cecilia M.

AU - Lu, Yingchang

AU - Madden, Pamela A. F.

AU - Montgomery, Grant W.

AU - Papanicolaou, George J.

AU - Raffel, Leslie J.

AU - Sacco, Ralph L.

AU - Sanchez, Elena

AU - Stark, Holger

AU - Sundstrom, Johan

AU - Taylor, Kent D.

AU - Xiang, Anny H.

AU - Zivkovic, Aleksandra

AU - Lind, Lars

AU - Ingelsson, Erik

AU - Martin, Nicholas G.

AU - Whitfield, John B.

AU - Cai, Jianwen

AU - Laurie, Cathy C.

AU - Okada, Yukinori

AU - Matsuda, Koichi

AU - Kooperberg, Charles

AU - Chen, Yii-der Ida

AU - Rundek, Tatjana

AU - Rich, Stephen S.

AU - Loos, Ruth J. F.

AU - Parra, Esteban J.

AU - Cruz, Miguel

AU - Rotter, Jerome I.

AU - Snieder, Harold

AU - Tomaszewski, Maciej

AU - Humphreys, Benjamin D.

AU - Franceschini, Nora

PY - 2019/12/1

Y1 - 2019/12/1

N2 - © 2019, The Author(s). 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.

AB - © 2019, The Author(s). 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.

KW - Adult

KW - Aged

KW - Blood Pressure/genetics

KW - Ethnic Groups/genetics

KW - Female

KW - Genetic Loci/genetics

KW - Genome-Wide Association Study

KW - Glomerular Filtration Rate/genetics

KW - Histone Code/genetics

KW - Histones/metabolism

KW - Humans

KW - Hypertension/ethnology

KW - Kidney Calculi/ethnology

KW - Kidney/physiopathology

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Renal Insufficiency, Chronic/ethnology

UR - http://www.scopus.com/inward/record.url?scp=85059496132&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07867-7

DO - 10.1038/s41467-018-07867-7

M3 - Article

C2 - 30604766

SN - 2041-1723

VL - 10

SP - 29

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 29

ER -

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

Abstract

Keywords

UN SDGs

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