How to Make DNA Methylome Wide Association Studies More Powerful

Abstract

Genome-wide association studies had a troublesome adolescence, while researchers increased statistical power, in part by increasing subject numbers. Interrogating the interaction of genetic and environmental influences raised new challenges of statistical power, which were not easily bested by the addition of subjects. Screening the DNA methylome offers an attractive alternative as methylation can be thought of as a proxy for the combined influences of genetics and environment. There are statistical challenges unique to DNA methylome data and also multiple features, which can be exploited to increase power. We anticipate the development of DNA methylome association study designs and new analytical methods, together with integration of data from other molecular species and other studies, which will boost statistical power and tackle causality. In this way, the molecular trajectories that underlie disease development will be uncovered.

Keywords::

• epigenome-wide association study (EWAS)
• developmental trajectories
• DNA methylation
• DNA methylation association studies (methWAS)
• epigenetic epidemiology
• gene × environment (GxE)

Financial & competing interests disclosure

This work is supported by the Translational Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease funded by the National Research Foundation (NRF) and administered by the National Medical Research Council (NMRC), (Singapore- NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014). SJ Barton is supported by the Epigen Consortium. This work was supported by grants from the Medical Research Council (MC_U147585827, MC_ST_U12055), British Heart Foundation (RG/07/009), Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, Cohen Trust, and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust. 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.

Additional information

Funding

This work is supported by the Translational Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease funded by the National Research Foundation (NRF) and administered by the National Medical Research Council (NMRC), (Singapore- NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014). SJ Barton is supported by the Epigen Consortium. This work was supported by grants from the Medical Research Council (MC_U147585827, MC_ST_U12055), British Heart Foundation (RG/07/009), Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, Cohen Trust, and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust. 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.