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

Research output: Contribution to journalArticlepeer-review

67 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 languageEnglish (US)
Article number1286
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
We thank the staff and participants of the ARIC study for their important contributions. The ARIC study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). We thank the staff and participants of the ARIC study for their important contributions. Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). The work of P.S. and A.K. was supported by the CRC 992 Initiative and by a Heisenberg Professorship (KO 3598/3-1 to A.K.) of the German Research Foundation (DFG). The FHS is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, and the NIH Director’s Challenge Award (PI: D. Levy). The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. Dr. Liang’s was supported by P30 DK46200 and partially supported by P30 DK46200. Work in the Susztak lab was supported by NIH DP3 DK108220 and NIH R01 DK087635. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Publisher Copyright:
© 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. © 2017 The Author(s).

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

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