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  • Original Article
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Novel associations between blood DNA methylation and body mass index in middle-aged and older adults

International Journal of Obesity volume 42, pages 887–896 (2018)Cite this article

Subjects

Abstract

Background/Objectives:

There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time.

Subjects/Methods:

Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case–control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis.

Results:

Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10−7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10−7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study.

Conclusions:

Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

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Acknowledgements

This work was supported by the Australian National Health and Medical Research Council (NHMRC) (grant 1088405). MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414 and by infrastructure provided by Cancer Council Victoria. Cases were ascertained through the Victorian Cancer Registry (VCR) and the Australian Cancer Database (Australian Institute of Health and Welfare). The nested case-control methylation studies were supported by the NHMRC grants 1011618, 1026892, 1027505, 1050198, 1043616 and 1074383. MCS is an NHMRC Senior Research Fellow (1061177). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding support for 'Building on GWAS for NHLBI-diseases: the US CHARGE consortium' was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Funding support for 'Building on GWAS for NHLBI-diseases: the US CHARGE consortium' was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). YMG was supported by a Radboud University Individual Travel Grant and funds from the Radboudumc Student budget. LB was supported by a Marie Curie International Incoming Fellowship within the 7th European Community Framework Programme. We thank the staff and participants of the MCCS and ARIC studies for their important contributions.

Author information

Author notes

  1. Y M Geurts and P-A Dugué: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia

    Y M Geurts, P-A Dugué, A M Hodge, J K Bassett, L M FitzGerald, R J MacInnis, G G Giles, D R English & R L Milne

  2. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia

    P-A Dugué, E Makalic, A M Hodge, D F Schmidt, D D Buchanan, R J MacInnis, J L Hopper, G G Giles, D R English & R L Milne

  3. Department of Pathology, Genetic Epidemiology Laboratory, University of Melbourne, Parkville, VIC, Australia

    J E Joo, E M Wong, H Tsimiklis & M C Southey

  4. Melbourne Bioinformatics, University of Melbourne, Parkville, VIC, Australia

    C-H Jung

  5. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    W Guan

  6. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    S Nguyen, J S Pankow & E W Demerath

  7. Department of Epidemiology, Human Genetics Center, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA

    M L Grove

  8. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

    L M FitzGerald

  9. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    L Baglietto

  10. Human Genetics Foundation (HuGeF), Torino, Italy

    G Severi

  11. CESP (U1018 INSERM, Équipe Générations et Santé), Facultés de médecine Université Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France

    G Severi

  12. Department of Pathology, Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, The University of Melbourne, Parkville, VIC, Australia

    D D Buchanan

  13. University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia

    D D Buchanan

  14. Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia

    D D Buchanan

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  1. Y M Geurts
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  2. P-A Dugué
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  8. M L Grove
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  10. A M Hodge
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  24. D R English
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Correspondence to R L Milne.

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Geurts, Y., Dugué, PA., Joo, J. et al. Novel associations between blood DNA methylation and body mass index in middle-aged and older adults. Int J Obes 42, 887–896 (2018). https://doi.org/10.1038/ijo.2017.269

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