Abstract
IntroductionDopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features, metabolic profiles, and dietary intake.MethodsAn adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened.ResultsAfter applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p < 0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (CACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the presence or absence of abdominal obesity. Pathway analyses revealed a statistically significant contribution of the aforementioned genes to dopaminergic synapse transmission (p = 4.78E−08). Furthermore, SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p < 0.001) and carbohydrate (p < 0.001) intakes.ConclusionsThe results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition.
Highlights
Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors
This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features and accompanying metabolic profiles as well as an epigenetic influence on macronutrient intake
Best Body mass index (BMI)-associated CpGs were selected according to stricter False Discovery Rate (FDR) values (p < 0.0001)
Summary
Further linear regression analyses adjusted by age and sex were performed to evaluate associations of methylation values at DA signaling genes with anthropometric measurements, the metabolic profile, and dietary intakes. AO: abdominal obesity; BMI: body mass index; DBP: diastolic blood pressure; HDL-c: high- density lipoprotein cholesterol; HOMA-IR index: homeostatic model assessment-insulin resistance index; LDL-c : low-d ensity lipoprotein cholesterol; SBP: systolic blood pressure; TC: total cholesterol; TG: triglycerides; TyG index: triglyceride-glucose index; WC: waist circumference. Pathway enrichment analyses revealed a significant contribution of BMI-associated genes to dopaminergic synapse transmission (p = 4.78E−08), involving complex interactions between presynaptic and postsynaptic cells (Figure 3) These genes modulated key processes involving physiological DA actions such as transport, uptake/reuptake, covalent modifications, and appropriate downstream signal flow. No relationships between methylation patterns of these CpG sites and protein or fat intakes were found
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