DNA methylation and obesity traits: An epigenome-wide association study. The REGICOR study

Abstract

Obesity is associated with increased risk of several diseases and has become epidemic. Obesity is highly heritable but the genetic variants identified by genome-wide association studies explain only limited variability. Epigenetics could contribute to explain the missing variability. The study aim was to discover differential methylation patterns related to obesity. We designed an epigenome-wide association study with a discovery phase in a subsample of 641 REGICOR study participants, validated by analysis of 2,515 participants in the Framingham Offspring Study. Blood DNA methylation was assessed using Illumina HumanMethylation450 BeadChip. Next, we meta-analyzed the data using the fixed effects method and performed a functional and pathway analysis using the Ingenuity Pathway Analysis software. We were able to validate 94 CpGs associated with body mass index (BMI) and 49 CpGs associated with waist circumference, located in 95 loci. In addition, we newly discovered 70 CpGs associated with BMI and 33 CpGs related to waist circumference. These CpGs explained 25.94% and 29.22% of the variability of BMI and waist circumference, respectively, in the REGICOR sample. We also evaluated 65 of the 95 validated loci in the GIANT genome-wide association data; 10 of them had Tag SNPs associated with BMI. The top-ranked diseases and functions identified in the functional and pathway analysis were neurologic, psychological, endocrine, and metabolic.

Insights into the multifactorial causation of obesity by integrated genetic and epigenetic analysis

“…Wahl et al 112 reported 187 methylation loci that were associated with BMI in blood and adipose tissue, but they did not estimate the amount of explained heritability. These results were further extended by Sayols‐Baixeras et al 113 They replicated the correlation between altered methylation and BMI or WC of previous EWASs for respectively 24 and 16 CpGs in blood samples. In combination with their newly identified methylation specific sites for BMI (70 CpGs) and WC (33 CpGs), obesity trait variability could be defined for respectively 14% and 17% 113 .…”

“…These results were further extended by Sayols‐Baixeras et al 113 They replicated the correlation between altered methylation and BMI or WC of previous EWASs for respectively 24 and 16 CpGs in blood samples. In combination with their newly identified methylation specific sites for BMI (70 CpGs) and WC (33 CpGs), obesity trait variability could be defined for respectively 14% and 17% 113 . The top hits of genome‐wide DNA methylation analyses appear to be enriched in obesity candidate genes as well as in genes involved in a wide variety of functions (immune response, gene transcription, cell differentiation, and epigenetic aging clock) 112–119 .…”

“…In combination with their newly identified methylation specific sites for BMI (70 CpGs) and WC (33 CpGs), obesity trait variability could be defined for respectively 14% and 17% 113 . The top hits of genome‐wide DNA methylation analyses appear to be enriched in obesity candidate genes as well as in genes involved in a wide variety of functions (immune response, gene transcription, cell differentiation, and epigenetic aging clock) 112–119 . These genes represent promising risk factors for the aetiology of obesity and could become the focus of further studies.…”

“…The epigenetic profile is not only influenced by environmental exposure, but likewise seems to be modulated by genetic variants 120 . Evidence is available that SNPs can affect methylation in nearby ( cis ) or distant ( trans ) CpGs, thus supporting the genotype‐epigenotype effect on complex traits 113, 115, 121–124 . Such variants are defined as methylation quantitative trait loci (meQTLs) and could offer some clarification for the unsolved previously identified GWAS polymorphisms.…”

Methylome-Wide Association Study of Central Adiposity Implicate Genes Involved in Immune and Endocrine Systems

“…Seven of these CpGs are novel central adiposity associations (near ADCY7, SREBF1, RAP1GAP2, and one intergenic), and cg19693031 near TXNIP, which is apparent across age and cohort. We additionally identified four CpG -central adiposity associations that were apparent across age and cohort, yet these effects were previously published for other obesity-related traits, such as BMI [11, 12, 16, 30-32, 34, 35], central obesity [12], overall obesity [12], and WC unadjusted for BMI [12,16,32,34].…”