Meta-Analysis

. 2021 Jun 28;12(1):3987.

doi: 10.1038/s41467-021-23899-y.

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Min-A Jhun^{1

2}, Michael Mendelson^{3

4}, Rory Wilson^{5

6}, Rahul Gondalia⁷, Roby Joehanes⁸, Elias Salfati⁹, Xiaoping Zhao¹⁰, Kim Valeska Emilie Braun¹¹, Anh Nguyet Do¹², Åsa K Hedman¹³, Tao Zhang¹⁴, Elena Carnero-Montoro^{15

16}, Jincheng Shen¹⁷, Traci M Bartz¹⁸, Jennifer A Brody¹⁹, May E Montasser^{20

21}, Jeff R O'Connell^{20

21}, Chen Yao³, Rui Xia¹⁰, Eric Boerwinkle²², Megan Grove²², Weihua Guan²³, Pfeiffer Liliane^{5

6}, Paula Singmann^{5

6}, Martina Müller-Nurasyid^{24

25

26}, Thomas Meitinger^{26

27

28}, Christian Gieger^{5

6}, Annette Peters^{6

26}, Wei Zhao²⁹, Erin B Ware^{29

30}, Jennifer A Smith^{29

30}, Klodian Dhana³¹, Joyce van Meurs³², Andre Uitterlinden³², Mohammad Arfan Ikram¹¹, Mohsen Ghanbari¹¹, Deugi Zhi³³, Stefan Gustafsson¹³, Lars Lind¹³, Shengxu Li¹⁴, Dianjianyi Sun^{14

34}, Tim D Spector¹⁵, Yii-der Ida Chen³⁵, Coleen Damcott^{20

21}, Alan R Shuldiner^{20

21}, Devin M Absher³⁶, Steve Horvath^{37

38}, Philip S Tsao^{9

39

40}, Sharon Kardia²⁹, Bruce M Psaty^{41

42}, Nona Sotoodehnia⁴³, Jordana T Bell¹⁵, Erik Ingelsson^{9

13

40

44}, Wei Chen¹⁴, Abbas Dehghan^{11

45}, Donna K Arnett¹², Melanie Waldenberger^{5

6}, Lifang Hou⁴⁶, Eric A Whitsel^{7

47}, Andrea Baccarelli^{48

49}, Daniel Levy^{3

50}, Myriam Fornage¹⁰, Marguerite R Irvin¹², Themistocles L Assimes^{51

52

53}

Affiliations

¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. mina.jhun82@gmail.com.
² Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. mina.jhun82@gmail.com.
³ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
⁵ Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
⁶ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
⁷ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁸ Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁹ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹¹ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹² Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
¹³ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁴ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
¹⁵ Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London, UK.
¹⁶ GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
¹⁷ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
¹⁸ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁰ Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
²¹ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
²² School of Public Health, University of Texas Health Science Center at Houston, Huston, TX, USA.
²³ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
²⁴ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁵ IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
²⁶ Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
²⁷ Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
²⁸ Institute of Human Genetics, Technical University Munich, Munich, Germany.
²⁹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁰ Survey Research Center, Institute for Social Research, Ann Arbor, MI, USA.
³¹ Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
³² Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
³³ School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA.
³⁴ Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
³⁵ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁶ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
³⁷ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³⁸ Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA.
³⁹ VA Palo Alto Healthcare System, Palo Alto, CA, USA.
⁴⁰ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
⁴¹ Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA, USA.
⁴² Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁴³ Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, WA, USA.
⁴⁴ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁴⁵ Department of Biostatistics and Epidemiology, MRC Centre for Environment and Health, School of Public Health, Imperial College, London, UK.
⁴⁶ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁴⁷ Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁴⁸ Department of Environmental Health Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA.
⁵⁰ Framingham Heart Study, Framingham, MA, USA.
⁵¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. tassimes@stanford.edu.
⁵² VA Palo Alto Healthcare System, Palo Alto, CA, USA. tassimes@stanford.edu.
⁵³ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. tassimes@stanford.edu.

PMID: 34183656
PMCID: PMC8238961
DOI: 10.1038/s41467-021-23899-y

Meta-Analysis

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Min-A Jhun et al. Nat Commun. 2021.

. 2021 Jun 28;12(1):3987.

doi: 10.1038/s41467-021-23899-y.

Authors

Affiliations

¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. mina.jhun82@gmail.com.
² Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. mina.jhun82@gmail.com.
³ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
⁵ Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
⁶ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
⁷ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁸ Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁹ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹¹ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹² Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
¹³ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁴ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
¹⁵ Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London, UK.
¹⁶ GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
¹⁷ Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
¹⁸ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁰ Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
²¹ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
²² School of Public Health, University of Texas Health Science Center at Houston, Huston, TX, USA.
²³ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
²⁴ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁵ IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
²⁶ Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
²⁷ Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
²⁸ Institute of Human Genetics, Technical University Munich, Munich, Germany.
²⁹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁰ Survey Research Center, Institute for Social Research, Ann Arbor, MI, USA.
³¹ Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
³² Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
³³ School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA.
³⁴ Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
³⁵ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁶ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
³⁷ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³⁸ Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA.
³⁹ VA Palo Alto Healthcare System, Palo Alto, CA, USA.
⁴⁰ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
⁴¹ Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA, USA.
⁴² Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁴³ Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, WA, USA.
⁴⁴ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁴⁵ Department of Biostatistics and Epidemiology, MRC Centre for Environment and Health, School of Public Health, Imperial College, London, UK.
⁴⁶ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁴⁷ Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁴⁸ Department of Environmental Health Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA.
⁵⁰ Framingham Heart Study, Framingham, MA, USA.
⁵¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. tassimes@stanford.edu.
⁵² VA Palo Alto Healthcare System, Palo Alto, CA, USA. tassimes@stanford.edu.
⁵³ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. tassimes@stanford.edu.

PMID: 34183656
PMCID: PMC8238961
DOI: 10.1038/s41467-021-23899-y

Erratum in

Publisher Correction: A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.
Jhun MA, Mendelson M, Wilson R, Gondalia R, Joehanes R, Salfati E, Zhao X, Braun KVE, Do AN, Hedman ÅK, Zhang T, Carnero-Montoro E, Shen J, Bartz TM, Brody JA, Montasser ME, O'Connell JR, Yao C, Xia R, Boerwinkle E, Grove M, Guan W, Liliane P, Singmann P, Müller-Nurasyid M, Meitinger T, Gieger C, Peters A, Zhao W, Ware EB, Smith JA, Dhana K, van Meurs J, Uitterlinden A, Ikram MA, Ghanbari M, Zhi D, Gustafsson S, Lind L, Li S, Sun D, Spector TD, Chen YI, Damcott C, Shuldiner AR, Absher DM, Horvath S, Tsao PS, Kardia S, Psaty BM, Sotoodehnia N, Bell JT, Ingelsson E, Chen W, Dehghan A, Arnett DK, Waldenberger M, Hou L, Whitsel EA, Baccarelli A, Levy D, Fornage M, Irvin MR, Assimes TL. Jhun MA, et al. Nat Commun. 2021 Jul 6;12(1):4256. doi: 10.1038/s41467-021-24600-z. Nat Commun. 2021. PMID: 34230475 Free PMC article. No abstract available.

Abstract

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.

PubMed Disclaimer

Conflict of interest statement

Alan R Shuldiner is an employee of Regeneron Pharmaceuticals, Inc. Bruce M Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Kim Valeska Emilie Braun works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc. and AXA. All other authors declare no competing interests. The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript.

Figures

**Fig. 1. Manhattan plots for the meta-analyses of the epigenome-wide association studies.**
Manhattan plots for (a) high-density lipoprotein (HDL), (b) low-density lipoprotein (LDL), and (c) triglycerides (TG) in European (N = 11,114), African (N = 4,452), and Hispanic (N = 699) populations. Results are plotted as negative log-transformed P values (y-axis) across the genome (x-axis). Odd chromosomes are in green and even chromosomes are in orange. The red horizontal line represents the epigenome-wide significance threshold of 1.09 × 10⁻⁷. Linear mixed effects models were implemented adjusting for age, sex (reference = male), smoking variable (never/previous/current, reference = never), lipid medication (Yes or No, reference = No), the top four principal components from genotypes (SNPs), the proportion of 5 types of cells estimated with the Houseman method (CD8 T lymphocytes, CD4 T lymphocytes, natural killer cells, B cells, and monocytes), and random effects for plate, row, and column, and BMI (model 4). The top CpGs of each chromosome were annotated with a gene name (in blue font: identified in a racial/ethnic group; red: identified in multiple racial/ethnic groups; bold: significantly associated with multiple lipid measures).

**Fig. 2. Scatter plots and regression lines of beta estimate pairs observed in two racial/ethnic groups for CpG-lipid trait associations.**
Plotted are betas from CpGs found to be significant (P < 1.09 × 10⁻⁷) in one or more racial/ethnic group. Plots and lines are shown between Europeans (EA) and African Americans (AA) (blue arrowheads/lines), Europeans (EA) and Hispanics (HA) (red triangles/lines), and African Americans (AA) and Hispanics (HA) (green diamonds/lines) for (a) high-density lipoprotein (HDL), (b) low-density lipoprotein (LDL), and (c) triglycerides (TG). Numerical regression slope and Pearson correlation coefficients are presented in the bottom right corner of each plot.

**Fig. 3. Venn diagram of genes identified through epigenome-wide association study of lipids and their overlap with other EWAS as well as genome-wide association studies of lipids.**
Genes identified in the racial/ethnic specific (European, African, and Hispanic) stratified meta-analysis of CpG-lipid associations involving either high-density lipoprotein (HDL), low-density lipoprotein (LDL), or triglycerides (TG) levels after adjusting for BMI and excluding subjects on statins. Genes identified in more than one racial/ethnic population are in bold font. Genes identified in EWAS of related cardiometabolic traits are marked with special characters: BMI (#), hepatic fat (*), fasting insulin or HOMA-IR ($), incident type2 diabetes (&), eGFR (^), blood pressure (%), C-reactive protein (CRP) (@), and cigarette smoking (+). Genes identified in previous GWAS are underlined.

See this image and copyright information in PMC

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A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Affiliations

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources