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

Olivia K L Hamilton,Stewart W Morris,David J Porteous,Andrew M Mcintosh,Ian J Deary,Riccardo E Marioni,Allan F Mcrae,Qian Zhang,Kathryn L Evans,Archie Campbell,Paul Redmond,Rosie M Walker,Alison D Murray

doi:10.1038/s41366-018-0262-3

Abstract

BackgroundThe 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.MethodAnalyses 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).ResultsA 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).ConclusionsWe 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.

Highlights

Body mass is a complex trait that demonstrates a high degree of variance in the general population [1]
Shah and colleagues [5] found that methylation profiles associated with body mass index (BMI) accounted for 6.9% of the variance in BMI, independently of genetic profiles, in a group of 1366 individuals from the Lothian Birth Cohort (LBC), which is the sample being studied in the present report
Phenotypic BMI was associated with greater time taken to walk 6 m (p = 2.6 × 10−16, R2 = 0.07), greater body weight (p < 2 × 10−16, R2 = 0.62), poorer general physical health (p = 7.1 × 10−11, R2 = 0.02), higher levels of %total HbA1c (p = 3.6 × 10−13, R2 = 0.06), higher levels of triglycerides (p = 2.2 × 10−15, R2 = 0.07), higher high-density lipoprotein cholesterol (HDL) ratio (p = 3.3 × 10−07, R2 = 0.03), lower levels of HDL cholesterol (p < 2 × 10−16, R2 = 0.08), poorer physical health-related quality of life (p = 1.3 × 10−14, R2 = 0.07), and lower levels of selfreported physical activity (p = 4.4 × 10−07, R2 = 0.03)

Summary

Introduction

Body mass is a complex trait that demonstrates a high degree of variance in the general population [1]. Shah and colleagues [5] found that methylation profiles associated with BMI accounted for 6.9% of the variance in BMI, independently of genetic profiles (polygenic scores), in a group of 1366 individuals from the Lothian Birth Cohort (LBC), which is the sample being studied in the present report. Epigenetic BMI score is associated with outcomes related to poor physical health, biomarkers of metabolic syndrome and social deprivation. Epigenetic BMI score was associated with lower physical health-related quality of life (p = 4 × 10−5, R2 = 0.02), lower scores on the Scottish Index of Multiple Deprivation (p = 9.9 × 10−05, R2 = 0.02), and lower levels of self-reported physical activity (p = 1.6 × 10−04, R2 = 0.02). Significant associations between epigenetic BMI score and outcome variables were tested for replication in an independent sample, the LBC1921.

Results

Discussion

Compliance with ethical standards