Elevated body mass index as a causal risk factor for symptomatic gallstone disease: A Mendelian randomization study

Elevated body mass index (BMI) is associated with an increased risk of gallstone disease. Whether this reflects a causal association is unknown. Using a Mendelian randomization approach, we studied 77,679 individuals from the general population. Of these, 4,106 developed symptomatic gallstone disease during up to 34 years of follow-up. Subjects were genotyped for three common variants known to associate with BMI: FTO(rs9939609); MC4R(rs17782313); and TMEM18(rs6548238). The number of BMI-increasing alleles was calculated for each participant. In observational analyses, mean baseline BMI was 55% (11.6 kg/m(2) ) increased in individuals in the fifth quintile versus the first quintile, similar in women and men. The corresponding multifactorially adjusted hazard ratio (HR) for symptomatic gallstone disease was 2.84 (95% confidence interval [CI]: 2.32-3.46) overall, 3.36 (95% CI: 2.62-4.31) in women, and 1.51 (95% CI: 1.09-2.11) in men (P trend: 0.001 to