Objective/methodsDNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples of human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese vs. obese individuals.ResultsWe identified negatively correlated methylation and expression of several obesity-associated genes in our discovery dataset and in silico replicated ETV6 in two independent cohorts. Further, we identified six adipose tissue depot-specific genes (HAND2, HOXC6, PPARG, SORBS2, CD36, and CLDN1). The effects were further supported in additional independent cohorts. Our top hits might play a role in adipogenesis and differentiation, obesity, lipid metabolism, and adipose tissue expandability. Finally, we show that in vitro methylation of SORBS2 directly represses gene expression.ConclusionsTaken together, our data show distinct tissue specific epigenetic alterations which associate with obesity.

BackgroundGenetic variants within the bitter taste receptor gene TAS2R38 are associated with sensitivity to bitter taste and are related to eating behavior in the Amish population. Sensitivity to bitter taste is further related to anthropometric traits in an genetically isolated Italian population. We tested whether the TAS2R38 variants (rs713598; rs1726866 and rs10246939) may be related to eating behavior, anthropometric parameters, metabolic traits and consumer goods intake in the German Sorbs.Materials and MethodsThe three SNPs were genotyped in a total cohort of 1007 individuals (male/female: 405/602). The German version of the three-factor eating questionnaire was completed by 548 individuals. Genetic association analyses for smoking behavior, alcohol and coffee intake, eating behavior factors (restraint, disinhibition and hunger) and other metabolic traits were analyzed. Further, by combining the three SNPs we applied comparative haplotype analyses categorizing PAV (proline-alanine-valine) carriers (tasters) vs. homozygous AVI (alanin-valine-isoleucine) carriers (non-tasters).ResultsSignificant associations of genetic variants within TAS2R38 were identified with percentage of body fat, which were driven by associations in women. In men, we observed significant associations with 30 min plasma glucose, and area under the curve for plasma glucose (0–120 min) (all adjusted P≤0.05). Further, we found that carriers of at least one PAV allele show significantly lower cigarette smoking per day (P = 0.002) as well as, albeit non-significant, lower alcohol intake. We did not confirm previously reported associations between genetic variants of TAS2R38 and eating behavior.ConclusionOur data suggest that genetic variation in TAS2R38 is related to individual body composition measures and may further influence consumer goods intake in the Sorbs possibly via individual sensitivity to bitter taste.

PurposeTo evaluate the coverage and accuracy of whole exome sequencing (WES) across vendors.MethodsBlood samples from three trios underwent WES at three vendors. Relative performance of the three WES services was measured for breadth and depth of coverage. The false-negative rates (FNR) were estimated using the segregation pattern within each trio.ResultsMean depth of coverage for all genes was 189.0, 124.9 and 38.3 for the three vendor services. Fifty-five of the ACMG 56 genes, but only 56 of 63 pharmacogenes were 100% covered at 10x in at least one of the nine individuals for all vendors; however, there was substantial inter-individual variability. For the two vendors with mean depth of coverage >120x, analytic positive predictive values (aPPV) exceeded 99.1% for SNVs and homozygous indels, and sensitivities were 98.9 – 99.9%; however, heterozygous indels showed lower accuracy and sensitivity. Among the trios, FNRs in the offspring were 0.07 – 0.62% at well-covered variants concordantly called in both parents.ConclusionThe current standard of 120x coverage for clinical WES may be insufficient for consistent breadth of coverage across the exome. Ordering clinicians and researchers would benefit from vendors’ reports that estimate sensitivity and aPPV, including depth of coverage across the exome.