There is an inverse relationship between serum bilirubin concentrations and risk of coronary artery disease. The strength of the association is similar to that of smoking, systolic blood pressure, and HDL cholesterol. We carried out a genomewide scan in a Framingham Heart Study. Our study sample consisted of 330 families with 1,394 sibling pairs, 681 cousin pairs, and 89 avuncular pairs. Using variance-component methods, the heritability was estimated to be 49%+/-6%, and the genome scan demonstrated significant evidence of linkage of serum bilirubin to chromosome 2q, with a LOD score of 3.8 at location 243 cM. The peak multipoint LOD score is located 1 cM away from the uridine diphosphate glycosyltransferase 1 (UGT1A1) gene. UGT1A1 catalyzes the conjugation of bilirubin with glucuronic acid and thus enhances bilirubin elimination; therefore, it is an important candidate gene for serum bilirubin. Gilbert syndrome, a hyperbilirubinemic syndrome, has a population frequency of 2%-19% and is mainly due to a TA insertion at the promoter region of UGT1A1. Only one other region in the genome produced a multipoint LOD score >1 (LOD = 1.3). Our findings suggest that UGT1A1 may be a major gene controlling serum bilirubin levels in the population.