Genome Medicine (Apr 2021)
Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci
- Charles E. Breeze,
- Anna Batorsky,
- Mi Kyeong Lee,
- Mindy D. Szeto,
- Xiaoguang Xu,
- Daniel L. McCartney,
- Rong Jiang,
- Amit Patki,
- Holly J. Kramer,
- James M. Eales,
- Laura Raffield,
- Leslie Lange,
- Ethan Lange,
- Peter Durda,
- Yongmei Liu,
- Russ P. Tracy,
- David Van Den Berg,
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed MESA Multi-Omics Working Group,
- Kathryn L. Evans,
- William E. Kraus,
- Svati Shah,
- Hermant K. Tiwari,
- Lifang Hou,
- Eric A. Whitsel,
- Xiao Jiang,
- Fadi J. Charchar,
- Andrea A. Baccarelli,
- Stephen S. Rich,
- Andrew P. Morris,
- Marguerite R. Irvin,
- Donna K. Arnett,
- Elizabeth R. Hauser,
- Jerome I. Rotter,
- Adolfo Correa,
- Caroline Hayward,
- Steve Horvath,
- Riccardo E. Marioni,
- Maciej Tomaszewski,
- Stephan Beck,
- Sonja I. Berndt,
- Stephanie J. London,
- Josyf C. Mychaleckyj,
- Nora Franceschini
Affiliations
- Charles E. Breeze
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services
- Anna Batorsky
- Department of Biostatistics, University of North Carolina
- Mi Kyeong Lee
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services
- Mindy D. Szeto
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus
- Xiaoguang Xu
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester
- Daniel L. McCartney
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
- Rong Jiang
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center
- Amit Patki
- Department of Biostatistics, University of Alabama
- Holly J. Kramer
- Department of Public Health Sciences and Medicine, Loyola University Chicago
- James M. Eales
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester
- Laura Raffield
- Department of Genetics, University of North Carolina
- Leslie Lange
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus
- Ethan Lange
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus
- Peter Durda
- Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont
- Yongmei Liu
- Duke Molecular Physiology Institute, Duke University Medical Center
- Russ P. Tracy
- Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont
- David Van Den Berg
- Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed MESA Multi-Omics Working Group
- Kathryn L. Evans
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
- William E. Kraus
- Duke Molecular Physiology Institute, Duke University Medical Center
- Svati Shah
- Duke Molecular Physiology Institute, Duke University Medical Center
- Hermant K. Tiwari
- Department of Biostatistics, University of Alabama
- Lifang Hou
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine
- Eric A. Whitsel
- Department of Epidemiology, University of North Carolina
- Xiao Jiang
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester
- Fadi J. Charchar
- School of Health and Life Sciences, Federation University Australia
- Andrea A. Baccarelli
- Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences and Epidemiology, Columbia University Mailman School of Public Health
- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia
- Andrew P. Morris
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester
- Marguerite R. Irvin
- Department of Epidemiology, University of Alabama at Birmingham
- Donna K. Arnett
- College of Public Health, University of Kentucky
- Elizabeth R. Hauser
- Duke Molecular Physiology Institute, Duke University Medical Center
- Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center
- Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles
- Riccardo E. Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
- Maciej Tomaszewski
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester
- Stephan Beck
- UCL Cancer Institute, University College London
- Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services
- Stephanie J. London
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services
- Josyf C. Mychaleckyj
- Center for Public Health Genomics, University of Virginia
- Nora Franceschini
- Department of Epidemiology, University of North Carolina
- DOI
- https://doi.org/10.1186/s13073-021-00877-z
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 16
Abstract
Abstract Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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