Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci

Ellen W Demerath¹, Weihua Guan², Megan L Grove³, Stella Aslibekyan⁴, Michael Mendelson⁵, Yi-Hui Zhou⁶, Åsa K Hedman⁷, Johanna K Sandling⁸, Li-An Li⁹, Marguerite R Irvin⁴, Degui Zhi¹⁰, Panos Deloukas¹¹, Liming Liang¹², Chunyu Liu¹³, Jan Bressler³, Tim D Spector¹⁴, Kari North¹⁵, Yun Li¹⁶, Devin M Absher¹⁷, Daniel Levy¹⁸, Donna K Arnett⁴, Myriam Fornage¹⁹, James S Pankow²⁰, Eric Boerwinkle¹⁹

Affiliations

¹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA, ewd@umn.edu.
² Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
³ Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
⁴ Department of Epidemiology and.
⁵ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA, Department of Cardiology, Boston Children's Hospital, Boston, MA 02215, USA.
⁶ Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA.
⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁸ Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹¹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
¹² Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA, Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA 02115, USA.
¹³ Framingham Heart Study, Framingham, MA 01702, USA, Department of Biostatistics, Boston University, Boston, MA 02118, USA.
¹⁴ Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
¹⁵ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁶ Department of Genetics, Department of Biostatistics and Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁷ Hudson Alpha Institute for Biotechnology, Huntsville, AL 34806, USA.
¹⁸ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA.
¹⁹ Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
²⁰ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.

PMID: 25935004
PMCID: PMC4492394
DOI: 10.1093/hmg/ddv161

Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci

Ellen W Demerath et al. Hum Mol Genet. 2015.

. 2015 Aug 1;24(15):4464-79.

doi: 10.1093/hmg/ddv161. Epub 2015 May 1.

Authors

Affiliations

¹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA, ewd@umn.edu.
² Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
³ Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
⁴ Department of Epidemiology and.
⁵ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA, Department of Cardiology, Boston Children's Hospital, Boston, MA 02215, USA.
⁶ Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA.
⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁸ Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹¹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
¹² Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA, Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA 02115, USA.
¹³ Framingham Heart Study, Framingham, MA 01702, USA, Department of Biostatistics, Boston University, Boston, MA 02118, USA.
¹⁴ Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
¹⁵ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁶ Department of Genetics, Department of Biostatistics and Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁷ Hudson Alpha Institute for Biotechnology, Huntsville, AL 34806, USA.
¹⁸ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824, USA, Framingham Heart Study, Framingham, MA 01702, USA.
¹⁹ Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
²⁰ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.

PMID: 25935004
PMCID: PMC4492394
DOI: 10.1093/hmg/ddv161

Abstract

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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Figures

**Figure 1.**
Flowchart of experiments and summary of results.

**Figure 2.**
Manhattan plot of CpG methylation association −log₁₀ P-values in 2107 African American adults in the ARIC study. (A) BMI and (B) WC.

**Figure 3.**
Overlap in EWAS results for BMI, WC and BMI change in ARIC African American adults.

See this image and copyright information in PMC

References

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Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci

Affiliations

Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

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LinkOut - more resources

Full Text Sources

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Medical

Molecular Biology Databases

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Miscellaneous