Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

CpG Islands DNA Methylation Epigenesis, Genetic Epigenomics / methods Gene Expression Regulation Genetic Variation Genetics, Population Genome-Wide Association Study Glomerular Filtration Rate Humans Kidney / metabolism Kidney Function Tests Phenotype Quantitative Trait Loci Quantitative Trait, Heritable Racial Groups / genetics
DNA methylation Epigenetic Gene regulation Kidney development Kidney function

Journal

Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844

Informations de publication

Date de publication:
30 04 2021
Historique:
received: 10 07 2020
accepted: 24 03 2021
entrez: 1 5 2021
pubmed: 2 5 2021
medline: 19 2 2022
Statut: epublish

Résumé

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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1186/s13073-021-00877-z PMID: 33931109 PMC: PMC8088054
pubmed: 33931109
doi: 10.1186/s13073-021-00877-z
pii: 10.1186/s13073-021-00877-z
pmc: PMC8088054
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

74

Subventions

Organisme : NHLBI NIH HHS
ID : U01 HL054472
Pays : United States
Organisme : NHLBI NIH HHS
ID : 75N92020C00005
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95168
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800015I
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800012I
Pays : United States
Organisme : CLC NIH HHS
ID : 75N90020D00002
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95167
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201600004C
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL055673
Pays : United States
Organisme : NIDA NIH HHS
ID : 75N95020D00004
Pays : United States
Organisme : NHLBI NIH HHS
ID : 75N92020C00006
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL054495
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800014I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201600001C
Pays : United States
Organisme : NHLBI NIH HHS
ID : 75N92020C00007
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100011I
Pays : United States
Organisme : Wellcome Trust
ID : 104036/Z/14/Z
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : HHSN268201600003C
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95169
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95161
Pays : United States
Organisme : NIMHD NIH HHS
ID : R01 MD012765
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079626
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95162
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800010I
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001420
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95165
Pays : United States
Organisme : British Heart Foundation
ID : PG/17/35/33001
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : HHSN268201600002C
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95159
Pays : United States
Organisme : British Heart Foundation
ID : PG/19/16/34270
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : N01HC95163
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117445
Pays : United States
Organisme : NHLBI NIH HHS
ID : 75N92020C00001
Pays : United States
Organisme : CLC NIH HHS
ID : 75N90020D00003
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201600018C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201500003I
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95164
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001079
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95166
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL054509
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000040
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL054473
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 218274/Z/19/Z
Pays : United Kingdom
Organisme : NIMHD NIH HHS
ID : HHSN268201800013I
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95160
Pays : United States

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Auteurs

Charles E Breeze (CE)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MD, USA. c.breeze@ucl.ac.uk.
UCL Cancer Institute, University College London, London, WC1E 6BT, UK. c.breeze@ucl.ac.uk.
Altius Institute for Biomedical Sciences, Seattle, WA, 98121, USA. c.breeze@ucl.ac.uk.
ORCID: 0000-0002-5294-915X

Anna Batorsky (A)

Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27516, USA.

Mi Kyeong Lee (MK)

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.

Mindy D Szeto (MD)

Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Xiaoguang Xu (X)

Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Daniel L McCartney (DL)

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.

Rong Jiang (R)

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, 27701, USA.

Amit Patki (A)

Department of Biostatistics, University of Alabama, Birmingham, AL, USA.

Holly J Kramer (HJ)

Department of Public Health Sciences and Medicine, Loyola University Chicago, Maywood, IL, USA.
Division of Nephrology and Hypertension, Loyola University Chicago, Maywood, IL, USA.

James M Eales (JM)

Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Laura Raffield (L)

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.

Leslie Lange (L)

Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Ethan Lange (E)

Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Peter Durda (P)

Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

Yongmei Liu (Y)

Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.

Russ P Tracy (RP)

Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

David Van Den Berg (D)

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.

Kathryn L Evans (KL)

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.

William E Kraus (WE)

Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
Division of Cardiology, Department of Medicine, School of Medicine, Duke University, Durham, NC, USA.

Svati Shah (S)

Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
Division of Cardiology, Department of Medicine, School of Medicine, Duke University, Durham, NC, USA.

Hermant K Tiwari (HK)

Department of Biostatistics, University of Alabama, Birmingham, AL, USA.

Lifang Hou (L)

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Center for Global Oncology, Institute of Global Health, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Eric A Whitsel (EA)

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
Department of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.

Xiao Jiang (X)

Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Fadi J Charchar (FJ)

School of Health and Life Sciences, Federation University Australia, Ballarat, VIC, Australia.
Department of Physiology, University of Melbourne, Parkville, VIC, Australia.
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Andrea A Baccarelli (AA)

Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences and Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA.

Stephen S Rich (SS)

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Andrew P Morris (AP)

Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.

Marguerite R Irvin (MR)

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Donna K Arnett (DK)

College of Public Health, University of Kentucky, Lexington, KY, USA.

Elizabeth R Hauser (ER)

Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
Durham VA Health System, Durham, NC, 27705, USA.

Jerome I Rotter (JI)

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.

Adolfo Correa (A)

Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.

Caroline Hayward (C)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.

Steve Horvath (S)

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, 90095, USA.

Riccardo E Marioni (RE)

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.

Maciej Tomaszewski (M)

Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Manchester Heart Centre and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.

Stephan Beck (S)

UCL Cancer Institute, University College London, London, WC1E 6BT, UK.

Sonja I Berndt (SI)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MD, USA.

Stephanie J London (SJ)

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.

Josyf C Mychaleckyj (JC)

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Nora Franceschini (N)

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. noraf@unc.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Ilots CpG › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Epigenome-wide association study of kidney...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Épigénomique › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Epigenome-wide association study of kidney...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génétique des populations › Epigenome-wide association study of kidney...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques des voies urinaires › Débit de filtration glomérulaire › Epigenome-wide association study of kidney...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Epigenome-wide association study of kidney...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › Epigenome-wide association study of kidney...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Techniques de diagnostic urologique › Tests de la fonction rénale › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › Epigenome-wide association study of kidney...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Caractère quantitatif héréditaire › Epigenome-wide association study of kidney...
questionsmedicales.fr › Personnes › Nord-Américains › Groupes de population aux États-Unis › Populations d'origine continentale › Epigenome-wide association study of kidney...