Methylome-Wide Association Study of Central Adiposity Implicates Genes Involved in Immune and Endocrine Systems

Abstract

Aim: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African–American adults in the Atherosclerosis Risk in Communities study. Materials & methods: We validated significantly associated cytosine–phosphate–guanine methylation sites (CpGs) among adults using the Women’s Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). Results & conclusion: We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1 and RAP1GAP2 that had not previously been associated with obesity-related traits.

Keywords::

• ancestrally diverse
• body fat distribution
• cardiometabolic disease
• central adiposity
• DNA methylation
• methylome-wide association study
• TXNIP
• waist circumference
• waist-to-height ratio
• waist-to-hip ratio

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2019-0276

Author contributions

Conceived of study design: AE Justice; drafted manuscript: AE Justice, G Chittoor, KE North; acquisition of data: AE Justice, KE North, R Gondalia, PE Melton, ML Grove, EA Whitse, C-T Liu, LA Cupples, W Guan, J Bressler, M Fornage, E Boerwinkle, Y Li, E Demerath, N Heard-Costa, D Levy, A Baccarelli, L Hou, K Conneely; data preparation: AE Justice, R Gondalia, N Heard-Costa; performed statistical analyses: AE Justice, G Chittoor, R Gondalia, L Fernandez-Rhodes, E Lim, N Heard-Costa, PE Melton; prepared figures and table: AE Justice, G Chittoor, L Fernandez-Rhodes, E Lim, N Heard-Costa; performed look-ups: AE Justice; supervised the work: KE North, EA Whitsel, E Demerath, Y Li, P Gordon-Larsen, AG Howard, CT Liu, LJ Beilin, TA Mori. All authors revised and approved the manuscript, assisted in interpretation of results and agree to be held accountable for the content.

Acknowledgments

The ARIC study. The authors thank the staff and participants of the ARIC study for their important contributions. The FHS Study. The authors thank the participants for the many years of commitment to the research conducted by the Framingham Heart Study. This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. The Raine study. The authors are grateful to The Raine study participants and their families, and the Raine study management team for cohort co-ordination and data collection, the National Health & Medical Research Council (NHMRC) for their long-term contribution to funding the study over the last 29 years and The Telethon Kids Institute for long-term support of the Study. The WHI study. The WHI program is supported by contracts from the National Heart, Lung and Blood Institute, NIH. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf

Financial & competing interests disclosure

AE Justice and analysis support was funded by K99/R00 HL130580. KE North was supported in part by R01HG010297. KE North, AG Howard, and P Gordon-Larsen were funded in part under NIH R01HL143885. The Atherosclerosis Risk in Communities (ARIC) 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). Funding was also supported by 5RC2HL102419 and R01NS087541.The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract no. N01-HC-25195, HHSN268201500001I and 75N92019D00031). The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. WHI-EMPC was supported by the NIH/NIEHS grant R01-ES020836 (L Hou, A Baccarelli, EA Whitsel). Funding for Core Management of The Raine Study is provided by The University of Western Australia (UWA), Raine Medical Research Foundation, The Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia, Raine Medical Research Foundation, and Curtin University. For Raine, the DNA methylation work was supported by NHMRC grant 1059711. Collaborative analyses are supported by NHMRC 1142858. Data collection and biological specimens at the 17-year follow-up were funded by the NHMRC Program Grant ID 353514 and Project Grant ID 403981. R-C Huang and TA Mori are supported by NHMRC Research Fellowships (ID 1053384 and ID 1136046, respectively). This work was supported by resources provided by The Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval from their respective institutions and all participants provided written informed consent. Also, for the Raine Study, the Human Ethics Committees of King Edward Memorial Hospital and Princess Margaret Hospital approved all protocols.

Data sharing statement

Summary statistics of all analyses are available upon request from the corresponding author.

Additional information

Funding

AE Justice and analysis support was funded by K99/R00 HL130580. KE North was supported in part by R01HG010297. KE North, AG Howard, and P Gordon-Larsen were funded in part under NIH R01HL143885. The Atherosclerosis Risk in Communities (ARIC) 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). Funding was also supported by 5RC2HL102419 and R01NS087541.The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract no. N01-HC-25195, HHSN268201500001I and 75N92019D00031). The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. WHI-EMPC was supported by the NIH/NIEHS grant R01-ES020836 (L Hou, A Baccarelli, EA Whitsel). Funding for Core Management of The Raine Study is provided by The University of Western Australia (UWA), Raine Medical Research Foundation, The Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia, Raine Medical Research Foundation, and Curtin University. For Raine, the DNA methylation work was supported by NHMRC grant 1059711. Collaborative analyses are supported by NHMRC 1142858. Data collection and biological specimens at the 17-year follow-up were funded by the NHMRC Program Grant ID 353514 and Project Grant ID 403981. R-C Huang and TA Mori are supported by NHMRC Research Fellowships (ID 1053384 and ID 1136046, respectively). This work was supported by resources provided by The Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.