Proportion of BMI Variance Explained in BSGS Adolescent Individuals
The methylation-profile scores derived from the MWAS analysis in the LBC individuals did not explain any variation (adjusted R2 = −0.001) in the sex- and age-adjusted BMI phenotype from the BSGS cohort, whereas that derived from the mostly middle-aged individuals of the LifeLines DEEP study explained 3.6% (p value = 8 × 10−5; Figure 2). Methylation scores based on the CpG probes identified in the larger Framingham MWAS but weighted with effect sizes from the older LBC individuals explained 3.0% of the variation in BMI in adolescent individuals. Based on the same CpG probes but effect sizes derived from the younger, albeit smaller, LifeLines DEEP cohort, the methylation-profile scores explained almost twice (5.4%) the variation in BMI in adolescent individuals (Figure 2).
Given that the proportion of variance explained in a prediction setting is a function of sample sizes of the discovery cohorts, the R2 values from different-sized cohorts are not directly comparable. We therefore compared the ratio of the methylation score R2 to the genetic score R2 to look at the relative contribution of the methylation- and genetic-profile scores to variance in BMI in both BSGS adolescents and older cohorts. As shown in Table S4, in all cases, the methylation-profile scores had a lower contribution to BMI variance in the BSGS cohort than in the other cohorts. The methylation predictor derived from older individuals (probes and weights for the methylation-profile score derived from the LBC MWAS) performed the worst.
A BMI methylation score based on a fixed-effect meta-analysis of the LBC and LifeLines DEEP MWAS results, whereby a Bonferroni correction for 374,629 common probes in the two cohorts (p value < 1.33 × 10−7) was used for selecting probes, performed better than the methylation score based on the LBC MWAS. However, despite the larger sample size, it performed worse than the predictor based on the LifeLines DEEP MWAS: its adjusted R2 was 0.028 (p value = 4.0 × 10−4).