Abstract
Obesity, as a metabolic disorder, can be either a cause or consequence of epigenetic alterations, but their temporal relationship is unknown. This study assessed the hypothesis that BMI and DNA methylation changes mutually influence each other, dependent on different methylation sites in the human genome. Peripheral leukocyte DNA methylation data on 294,840 CpG sites filtered from 485,577 sites generated by Illumina 450K BeadChip were analyzed in two discovery cohorts (585 whites and 245 blacks) and a longitudinal cohort (95 whites and 43 blacks followed 3.2 years) in the Bogalusa Heart Study (BHS) and 2 replication cohorts (450 twins in Chinese National Twin Study, 456 blacks in Georgia Prevention Institute Epigenetics of Obesity Study). BMI was significantly associated with methylation levels at cg17260706 (negatively), cg13562284 (negatively) and cg15721584 (positively) consistently in the discovery cohorts, and these associations were replicated in both 450 Chinese twins and 456 blacks in the same directions. The temporal relationship analyses in a cross-lagged path analysis model showed a one-directional relation from BMI to methylation changes at cg17260706 in BCL9L gene in both races as seen in the figure. The temporal relationship was different in blacks versus whites for the other two CpGs. In longitudinal analysis of BMI measured 4 or more times over 40 years in the BHS, childhood (p<0.05) and adulthood BMI (p<0.01) and its long-term burden (p<0.01) and increasing trend (p<0.01) were all negatively associated with the methylation level at cg17260706 in 615 whites and 276 blacks. In addition, an SNP in the BCL9L gene (rs586763) was associated with the methylation level at cg17260706 (p<0.05) in blacks only; decreasing slopes of the methylation level at cg17260706 with increasing BMI were significantly different in three genotype groups in blacks (p<0.05), but not in whites. In conclusion, higher BMI results in lower methylation levels at cg17260706 in the BCL9L gene.
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