Such an approach, however, does not consider synchronous correlations and self-tracking over time for closely intercorrelated variables, 18– 21 which complicates causal inference. 15 used a change-by-change (i.e., change in BMI and change in DNAm) approach and found that baseline DNAm levels at several loci (e.g., NFATC2IP-cg26663590 15, ABCG1-cg06500161, DHCR24-cg17901584, NDST4-cg07235935, and MYO5C-cg06192883 17) were predictors for changes in BMI.
These studies have employed statistical modeling, including Mendelian randomisation 13– 15 and twins-study based regression 16, in cross-sectional studies. 12 In the case of obesity, several epigenome-wide association studies (EWASs) have reported that changes in DNAm levels at identified CpG sites are likely to be the consequence, not causes, of obesity.
The temporal sequence between DNAm and chronic diseases is uncertain, due to plasticity in DNAm in response to environmental changes. 10 Epigenetic changes are also thought to contribute to the missing heritability. 8, 9 Epigenetic changes, in particular changes in DNA methylation (DNAm), reflect effects of environmental changes on the human genome and may underline the link between obesity and environmental factors. 7 It is widely recognized that environmental factors, such as lack of physical activity and increased energy intake, have been the driving force for the current obesity epidemic. 5 Although it is estimated that 40-70% of variability in body mass index (BMI), a common measure to assess general obesity, is explained by genetic factors, 6 only ~6% of variance in BMI is explained by genetic variants identified in the largest genome-wide association study to date. 1– 4 Etiology of human obesity is complex. Obesity is a major public health challenge due to its high prevalence and related adverse health consequences. Baseline BMI was associated with a DNAm score (calculated from DNAm levels at the associated CpG sites) at follow-up (P < 0.001 both in Blacks and in Whites).
Cross-lagged panel analyses showed significant unidirectional paths (P FDR < 0.05) from baseline BMI to follow-up DNAm at 18 CpG sites in Whites and 7 in Blacks no CpG sites showed significant paths from DNAm at baseline to BMI at follow-up. In discovery and replication samples, 349 CpG sites (266 novel) in Whites and 36 (21 novel) in Blacks were identified to be robustly associated with BMI, with 8 (1 novel) CpG sites overlapping between the two races. Cross-lagged panel analysis was used to examine the temporal relationship between DNAm and BMI in 439 Whites and 201 Blacks who were examined twice 6.2 years apart. Suggestive CpG sites were further replicated in 252 Whites and 228 Blacks from the Georgia Stress and Heart Study. Race-specific EWASs were performed in 995 Whites and 490 Blacks from the Bogalusa Heart Study.
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