An epigenetic score for BMI based on DNA methylation correlates with poor physical health and major disease in the Lothian Birth Cohort

Abstract

Background: The relationship between obesity and adverse health is well established, but little is known about the contribution of DNA methylation to obesity-related health outcomes. This study tests associations between an epigenetic score for body mass index (BMI) and health-related, cognitive, psychosocial and lifestyle outcomes in the Lothian Birth Cohort 1936. This study also tests whether these associations are independent of phenotypic BMI.

Method: Analyses were conducted using data from the Lothian Birth Cohort 1936 (n = 892). Weights for the epigenetic BMI score were derived using penalised regression on methylation data from unrelated Generation Scotland participants (n = 2562). Associations were tested for replication in an independent sample: the Lothian Birth Cohort 1921 (n = 433).

Results: A higher epigenetic BMI score was associated with higher BMI (R² = 0.1), greater body weight (R² = 0.06), greater time taken to walk 6 m, poorer lung function and poorer general physical health (all R² = 0.02), greater levels of triglycerides (R² = 0.09), greater %total HbA1c (R² = 0.06), lower levels of high-density lipoprotein cholesterol (HDL; R² = 0.08), higher HDL ratio (HDL/total cholesterol; R² = 0.03), lower health-related quality of life, physical inactivity, and greater social deprivation (all R² = 0.02). The epigenetic BMI score (per SD) was also associated with type 2 diabetes (OR 2.17, 95% CI 1.67, 2.84), cardiovascular disease (OR 1.45, 95% CI 1.24, 1.71) and high blood pressure (OR 1.30, 95% CI 1.13, 1.49; all p < 0.00026 after Bonferroni correction). Associations were replicated for BMI (R² = 0.06), body weight (R² = 0.04), health-related quality of life (R² = 0.02), HbA1c (R² = 0.07) and triglycerides (R² = 0.07; all p < 0.0045 after Bonferroni correction).

Conclusions: We observed and replicated associations between an epigenetic score for BMI and variables related to poor physical health and metabolic syndrome. Regression models with both epigenetic and phenotypic BMI scores as predictors accounted for a greater proportion of variance in all outcome variables than either predictor alone, demonstrating independent and additive effects of epigenetic and phenotypic BMI scores.

Fig. 1

Plot of R² statistics from linear regression analyses in which epigenetic BMI, phenotypic BMI and epigenetic + phenotypic BMI, respectively, associated with biomarker variables at p < 0.00026. The plots demonstrate the general pattern observed, with the additive model accounting for a greater proportion of variance in the outcome variable  than models including epigenetic BMI score only, or phenotypic BMI only