Since there have not been any studies that quantify the influence of genetic factors on gallbladder disease (GBD) in humans using information from families, we utilized pedigree data to explore the genetic control of variation in liability to GBD. Using an extension of a variance components approach, we performed genetic analyses of GBD using information from 32 low-income Mexican-American families with two slightly different general models incorporating several sex-specific GBD risk factors. After evaluating the relative magnitudes of the covariate effects from these two models, we identified a parsimonious model including only significant predictors of GBD. According to this model, heritability for GBD was high (h2 = 0.44+/-0.18), after accounting for the significant effects of age, leptin in both sexes, total cholesterol, and HDL cholesterol in males only. We have shown quantitatively that variation in GBD is under strong genetic control. However, there are two major limitations to our findings: (1) since GBD was defined by a self-reported clinical history rather than an ultrasound examination, the prevalence of GBD could have been underestimated; and (2) since our design did not allow for shared environmental effects, our estimate of heritability may have been inflated.