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Obesity is a multifactorial condition influenced by both genetics and lifestyle. The aim of this study was to investigate whether the association between a validated genetic profile risk score for obesity (GPRS-obesity) and body mass index (BMI) or waist circumference (WC) was modified by macronutrient intake in a large general population study.This study included cross-sectional data from 48 170 white European adults, aged 37-73 years, participating in the UK Biobank. Interactions between GPRS-obesity and macronutrient intake (including total energy, protein, fat, carbohydrate and dietary fibre intake) and its effects on BMI and WC were investigated.The 93-single-nucleotide polymorphism (SNP) GPRS was associated with a higher BMI (β: 0.57 kg m-2 per s.d. increase in GPRS (95% confidence interval: 0.53-0.60); P = 1.9 × 10-183) independent of major confounding factors. There was a significant interaction between GPRS and total fat intake (P(interaction) = 0.007). Among high-fat-intake individuals, BMI was higher by 0.60 (0.52, 0.67) kg m-2 per s.d. increase in GPRS-obesity; the change in BMI with GPRS was lower among low-fat-intake individuals (β: 0.50 (0.44, 0.57) kg m-2). Significant interactions with similar patterns were observed for saturated fat intake (high β: 0.66 (0.59, 0.73) versus low β: 0.49 (0.42, 0.55) kg m-2, P(interaction) = 2×10-4) and for total energy intake (high β: 0.58 (0.51, 0.64) versus low β: 0.49 (0.42, 0.56) kg m-2, P(interaction) = 0.019), but not for protein intake, carbohydrate intake and fibre intake (P(interaction) >0.05). The findings were broadly similar using WC as the outcome.These data suggest that the benefits of reducing the intake of fats and total energy intake may be more important in individuals with high genetic risk for obesity.