Epigenome-wide association studies identify DNA methylation associated with kidney function

Audrey Y. Chu; Adrienne Tin; Pascal Schlosser; Yi An Ko; Chengxiang Qiu; Chen Yao; Roby Joehanes; Morgan E. Grams; Liming Liang; Caroline A. Gluck; Chunyu Liu; Josef Coresh; Shih Jen Hwang; Daniel Levy; Eric Boerwinkle; James S. Pankow; Qiong Yang; Myriam Fornage; Caroline S. Fox; Katalin Susztak; Anna Köttgen

doi:10.1038/s41467-017-01297-7

Epigenome-wide association studies identify DNA methylation associated with kidney function

Audrey Y. Chu, Adrienne Tin, Pascal Schlosser, Yi An Ko, Chengxiang Qiu, Chen Yao, Roby Joehanes, Morgan E. Grams, Liming Liang, Caroline A. Gluck, Chunyu Liu, Josef Coresh, Shih Jen Hwang, Daniel Levy, Eric Boerwinkle, James S. Pankow, Qiong Yang, Myriam Fornage, Caroline S. Fox, Katalin SusztakAnna Köttgen

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

Abstract

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.

Original language	English (US)
Article number	1286
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01297-7
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Chu, A. Y., Tin, A., Schlosser, P., Ko, Y. A., Qiu, C., Yao, C., Joehanes, R., Grams, M. E., Liang, L., Gluck, C. A., Liu, C., Coresh, J., Hwang, S. J., Levy, D., Boerwinkle, E., Pankow, J. S., Yang, Q., Fornage, M., Fox, C. S., ... Köttgen, A. (2017). Epigenome-wide association studies identify DNA methylation associated with kidney function. Nature communications, 8(1), Article 1286. https://doi.org/10.1038/s41467-017-01297-7

Chu, AY, Tin, A, Schlosser, P, Ko, YA, Qiu, C, Yao, C, Joehanes, R, Grams, ME, Liang, L, Gluck, CA, Liu, C, Coresh, J, Hwang, SJ, Levy, D, Boerwinkle, E, Pankow, JS, Yang, Q, Fornage, M, Fox, CS, Susztak, K & Köttgen, A 2017, 'Epigenome-wide association studies identify DNA methylation associated with kidney function', Nature communications, vol. 8, no. 1, 1286. https://doi.org/10.1038/s41467-017-01297-7

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title = "Epigenome-wide association studies identify DNA methylation associated with kidney function",

abstract = "Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.",

author = "Chu, {Audrey Y.} and Adrienne Tin and Pascal Schlosser and Ko, {Yi An} and Chengxiang Qiu and Chen Yao and Roby Joehanes and Grams, {Morgan E.} and Liming Liang and Gluck, {Caroline A.} and Chunyu Liu and Josef Coresh and Hwang, {Shih Jen} and Daniel Levy and Eric Boerwinkle and Pankow, {James S.} and Qiong Yang and Myriam Fornage and Fox, {Caroline S.} and Katalin Susztak and Anna K{\"o}ttgen",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s). Genome-wide association studies of kidney function show enrichment of associated genetic variants in regulatory regions. Here, the authors perform epigenome-wide association studies of kidney function and disease, identifying 19 CpG sites significantly associated with these. {\textcopyright} 2017 The Author(s).",

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AU - Schlosser, Pascal

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AU - Qiu, Chengxiang

AU - Yao, Chen

AU - Joehanes, Roby

AU - Grams, Morgan E.

AU - Liang, Liming

AU - Gluck, Caroline A.

AU - Liu, Chunyu

AU - Coresh, Josef

AU - Hwang, Shih Jen

AU - Levy, Daniel

AU - Boerwinkle, Eric

AU - Pankow, James S.

AU - Yang, Qiong

AU - Fornage, Myriam

AU - Fox, Caroline S.

AU - Susztak, Katalin

AU - Köttgen, Anna

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N2 - Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.

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Epigenome-wide association studies identify DNA methylation associated with kidney function

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