Objectives To evaluate the joint (combined) association of excess adiposity and genetic predisposition with the risk of incident female gout, and compare to their male counterparts; and determine the proportion attributable to body mass index (BMI) only, genetic risk score (GRS) only, and to their interaction.

Methods We prospectively investigated potential gene-BMI interactions in 18 244 women from the Nurses’ Health Study and compared with 10 888 men from the Health Professionals Follow-Up Study. GRS for hyperuricaemia was derived from 114 common urate-associated single nucleotide polymorphisms.

Results Multivariable relative risk (RR) for female gout was 1.49 (95% CI 1.42 to 1.56) per 5 kg/m² increment of BMI and 1.43 (1.35 to 1.52) per SD increment in the GRS. For their joint association of BMI and GRS, RR was 2.18 (2.03 to 2.36), more than the sum of each individual factor, indicating significant interaction on an additive scale (p for interaction <0.001). The attributable proportions of joint effect for female gout were 42% (37% to 46%) to adiposity, 37% (32% to 42%) to genetic predisposition and 22% (16% to 28%) to their interaction. Additive interaction among men was smaller although still significant (p interaction 0.002, p for heterogeneity 0.04 between women and men), and attributable proportion of joint effect was 14% (6% to 22%).

Conclusions While excess adiposity and genetic predisposition both are strongly associated with a higher risk of gout, the excess risk of both combined was higher than the sum of each, particularly among women.