Inference about causation between body mass index and DNA methylation in blood from a twin family study

• DOI: 10.1038/s41366-018-0103-4
• Publication Date: 2018-05-17T13:35:50Z
• Authors: Shuai Li; Ee Ming Wong; Minh Bui; Tuong L Nguyen; Ji-Hoon Eric Joo; Jennifer Stone; Gillian S Dite; Pierre-Antoine Dugué; Roger L Milne; Graham G Giles; Richard Saffery; Melissa C Southey; John L Hopper
• Keywords: Adult; Epigenomics; 0301 basic medicine; 2. Zero hunger; Adolescent; Australia; Twins, Monozygotic; DNA Methylation; Middle Aged; Body Mass Index; Young Adult; 03 medical and health sciences; Cross-Sectional Studies; Twins, Dizygotic; Humans; Genome-Wide Association Study

AbstractBackgroundSeveral studies have reported DNA methylation in blood to be associated with body mass index (BMI), but only a few have investigated causal aspects of the association. We used a twin family design to assess this association at two life points and applied a novel analytical approach to investigate the evidence for causality.MethodsThe methylation profile of DNA from peripheral blood was measured for 479 Australian women (mean age 56 years) from 130 twin families. Linear regression was used to estimate the associations of methylation at ~410 000 cytosine-guanine dinucleotides (CpG), and of the average methylation at ~20 000 genes, with current BMI, BMI at age 18-21 years, and the change between the two (BMI change). A novel regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess causation.ResultsAt 5% false discovery rate, nine, six and 12 CpGs at 24 loci were associated with current BMI, BMI at age 18-21 years and BMI change, respectively. The average methylation ofBHLHE40andSOCS3loci was associated with current BMI, and ofPHGDHlocus was associated with BMI change. From the ICE FALCON analyses with BMI as the predictor and methylation as the outcome, a woman’s methylation level was associated with her co-twin’s BMI, and the association disappeared conditioning on her own BMI, consistent with BMI causing methylation. To the contrary, using methylation as the predictor and BMI as the outcome, a woman’s BMI was not associated with her co-twin’s methylation level, consistent with methylation not causing BMI.ConclusionFor middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with current BMI, BMI at age 18-21 years and BMI change. Our study suggests that BMI has a causal effect on peripheral blood DNA methylation.