Obesity is a multifactorial condition arising from the interaction between genetic and lifestyle factors. We aimed to assess the impact of lifestyle and genetic factors on obesity-related traits in 302 healthy Ghanaian adults. Dietary intake and physical activity were assessed using a 3 day repeated 24 h dietary recall and global physical activity questionnaire, respectively. Twelve single nucleotide polymorphisms (SNPs) were used to construct 4-SNP, 8-SNP and 12-SNP genetic risk scores (GRSs). The 4-SNP GRS showed significant interactions with dietary fat intakes on waist circumference (WC) (Total fat, P = 0.01; saturated fatty acids (SFA), P = 0.02; polyunsaturated fatty acids (PUFA), P = 0.01 and monounsaturated fatty acids (MUFA), P = 0.01). Among individuals with higher intakes of total fat (>47 g/d), SFA (>14 g/d), PUFA (>16 g/d) and MUFA (>16 g/d), individuals with ≥3 risk alleles had a significantly higher WC compared to those with <3 risk alleles. This is the first study of its kind in this population, suggesting that a higher consumption of dietary fatty acid may have the potential to increase the genetic susceptibility of becoming centrally obese. These results support the general dietary recommendations to decrease the intakes of total fat and SFA, to reduce the risk of obesity, particularly in individuals with a higher genetic predisposition to central obesity.