INTRODUCTION: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, metabolic profiles, and dietary intake. METHODS:An 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. RESULTS:After 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. CONCLUSIONS:The 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.