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

^*Corresponding author for this work

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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 language	English
Article number	29
Number of pages	14
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-018-07867-7
Publication status	Published - 3 Jan 2019

Keywords

Chronic kidney disease
Genome-wide association studies
Quantitative trait
Podocytes

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1 Active

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. & Davey Smith, G.
1/04/18 → 31/03/23
Project: Research

Professor George Davey Smith
- KZ.Davey-Smith@bristol.ac.uk
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
- Elizabeth Blackwell Institute for Health Research
- Cancer
- Bristol Medical School (PHS) - Professor of Clinical Epidemiology
Person: Academic , Member, Group lead
Dr Gibran Hemani
- g.hemani@bristol.ac.uk
- Bristol Medical School (PHS) - Senior Research Fellow
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
Person: Academic , Member

Cite this

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, [29]. https://doi.org/10.1038/s41467-018-07867-7

Morris, Andrew P. ; Le, Thu H. ; Wu, Haojia ; Akbarov, Artur ; van der Most, Peter J. ; Hemani, Gibran ; Smith, George Davey ; Mahajan, Anubha ; Gaulton, Kyle J. ; Nadkarni, Girish N. ; Valladares-Salgado, Adan ; Wacher-Rodarte, Niels ; Mychaleckyj, Josyf C. ; Dueker, Nicole D. ; Guo, Xiuqing ; Hai, Yang ; Haessler, Jeffrey ; Kamatani, Yoichiro ; Stilp, Adrienne M. ; Zhu, Gu ; Cook, James P. ; Ärnlöv, Johan ; Blanton, Susan H. ; de Borst, Martin H. ; Bottinger, Erwin P. ; Buchanan, Thomas A. ; Cechova, Sylvia ; Charchar, Fadi J. ; Chu, Pei Lun ; Damman, Jeffrey ; Eales, James ; Gharavi, Ali G. ; Giedraitis, Vilmantas ; Heath, Andrew C. ; Ipp, Eli ; Kiryluk, Krzysztof ; Kramer, Holly J. ; Kubo, Michiaki ; Larsson, Anders ; Lindgren, Cecilia M. ; Lu, Yingchang ; Madden, Pamela A.F. ; Montgomery, Grant W. ; Papanicolaou, George J. ; Raffel, Leslie J. ; Sacco, Ralph L. ; Sanchez, Elena ; Stark, Holger ; Sundstrom, Johan ; Taylor, Kent D. ; Xiang, Anny H. ; Zivkovic, Aleksandra ; Lind, Lars ; Ingelsson, Erik ; Martin, Nicholas G. ; Whitfield, John B. ; Cai, Jianwen ; Laurie, Cathy C. ; Okada, Yukinori ; Matsuda, Koichi ; Kooperberg, Charles ; Chen, Yii Der Ida ; Rundek, Tatjana ; Rich, Stephen S. ; Loos, Ruth J.F. ; Parra, Esteban J. ; Cruz, Miguel ; Rotter, Jerome I. ; Snieder, Harold ; Tomaszewski, Maciej ; Humphreys, Benjamin D. ; Franceschini, Nora. / Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies. In: Nature Communications. 2019 ; Vol. 10.

@article{c0f1759cd79f43c8a2d6f0dc797d807d,

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

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.",

keywords = "Chronic kidney disease, Genome-wide association studies, Quantitative trait, Podocytes",

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 Chu, {Pei Lun} 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",

year = "2019",

month = jan,

day = "3",

doi = "10.1038/s41467-018-07867-7",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

}

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, PL, 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, YDI, 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, 29. https://doi.org/10.1038/s41467-018-07867-7

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

In: Nature Communications, Vol. 10, 29, 03.01.2019.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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 - 2019/1/3

Y1 - 2019/1/3

N2 - 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 - 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 - Chronic kidney disease

KW - Genome-wide association studies

KW - Quantitative trait

KW - Podocytes

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 (Academic Journal)

C2 - 30604766

AN - SCOPUS:85059496132

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 29

ER -

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

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Professor George Davey Smith

Dr Gibran Hemani

Cite this