Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci
Open accessAbstract
Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
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Numerous EWAS have identified leukocyte-based DNA methylation markers associated with disease traits.
“numerous studies have successfully identified leukocyte-based DNAm markers associated with disease traits (Demerath et al., 2015; Dick et al., 2014; Hidalgo et al., 2014; Irvin et al., 2014; Liang et al., 2015; Liu, Aryee, et al., 2013).”
From Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016) · cites this paper as Demerath et al., 2015
EWAS identified DNA methylation sites with much larger effect sizes compared to a typical GWAS of the same trait.
“Using hundreds to thousands of subjects, these EWAS identified DNAm sites with much larger effect sizes compared to a typical GWAS of the same trait (Demerath et al., 2015; Dick et al., 2014).”
From Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016) · cites this paper as Demerath et al., 2015
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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
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Precision medicine in adult and pediatric obesity: a clinical perspective
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Epigenome modifiers and metabolic rewiring: New frontiers in therapeutics
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- Authors
- Demerath, E. W., Guan, W., Grove, M. L., Aslibekyan, S., Mendelson, M., Zhou, Y.-H., Hedman, Å. K., Sandling, J. K., Li, L.-A., Irvin, M. R., Zhi, D., Deloukas, P., Liang, L., Liu, C., Bressler, J., Spector, T. D., North, K., Li, Y., Absher, D. M., Levy, D., Arnett, D. K., Fornage, M., Pankow, J. S., & Boerwinkle, E.
- Affiliations
- University of Minnesota (US)
- The University of Texas Health Science Center at Houston (US)
- Boston Children's Hospital (US)
- North Carolina State University (US)
- Uppsala University (SE)
- Baylor College of Medicine (US)
- University of Alabama at Birmingham (US)
- Queen Mary University of London (GB)
- National Institutes of Health (US)
- Boston University (US)
- King's College London (GB)
- University of North Carolina at Chapel Hill (US)
- HudsonAlpha Institute for Biotechnology (US)
- Corresponding author
- Demerath, Ellen W.
- ORCID
- Demerath, Ellen W.
- Guan, Weihua
- Grove, Megan L.
- Aslibekyan, Stella
- Mendelson, Michael
- Zhou, Yi-Hui
- Hedman, Åsa K.
- Sandling, Johanna K.
- Irvin, Marguerite R.
- Zhi, Degui
- Deloukas, Panos
- Liang, Liming
- Liu, Chunyu
- Bressler, Jan
- Spector, Tim D.
- North, Kari
- Li, Yun
- Absher, Devin M.
- Levy, Daniel
- Arnett, Donna K.
- Fornage, Myriam
- Pankow, James S.
- Boerwinkle, Eric
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-05-01
- Volume
- 24
- Issue
- 15
- Pages
- 4464-4479
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4492394
- OpenAlex
- W2116790770
- Cited by
- 355
- References
- 92
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 23 · 2023: 40 · 2022: 32 · 2021: 36 · 2020: 35 · 2019: 43 · 2018: 31 · 2017: 50 · 2016: 38 · 2015: 4
- FWCI
- 17.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Wellcome Trust (FP7/2007–2013)
- National Institute for Health and Care Research (FP7/2007–2013, NF-SI-0514-10027)
- King's College London
- National Institutes of Health (HHSN268201100012C, FP7/2007-2013, HHSN268201100008C, HHSN26820- 1100005C, HHSN268201100007C, HHSN268201100011C, HHSN268201100010C, n01hc25195-41-0-1, HHSN268201100009C, N01-HC 25195)
- U.S. Public Health Service (HHSN268201100012C), HHSN2682 01100010C, HHSN268201100007 C, HHSN2682011-00008C, HHSN268201100 006C, HHSN2682‐01100011C, HHSN268201100009C, HHSN 268201100005C)
- National Heart, Lung, and Blood Institute (HHSN268201 100012C, HHSN268201100007C, HHSN2682 01100008C, HH-SN-268201100006C, HHSN268201100011C, N01‐HC25195, HHSN268201100005C, HHSN268201100010C, U01HL072524, HHSN26820 1100009C, R01HL104135, RC2HL102419)
- Center for Information Technology
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- obesity, body mass index, waist circumference, BMI change, DNA methylation, epigenome-wide association study, African American adults, HIF-3α, CPT1A, ABCG1, LGALS3BP, KDM2B, PBX1, BBS2, lipid metabolism, immune response, cytokine signaling, tissue-specific methylation
- MeSH terms
- Aged, Black or African American, Female, Humans, Male, Middle Aged, Obesity, Body Mass Index, DNA Methylation, Epigenesis, Genetic, White People, Atherosclerosis, Lipid Metabolism, Metabolic Networks and Pathways, Waist Circumference, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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