We have examined the possible linkage of adrenocorticotropin receptor/melanocortin receptor-2 (ACTHR/MC-2) to a reported putative susceptibility locus for bipolar illness (BP) in 20 affected pedigrees. Initially, allelic variants of the gene were identified by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) and the gene was genetically mapped using both the Centre d'Etudes du Polymorphisme Humain (CEPH) pedigrees and the BP pedigrees used in this study. We found that the ACTHR/MC-2 gene maps between D18S53 and D18S66. These loci span a region of chromosome 18 which, in a previous study [Berrettini et al.: Proc Natl Acad Sci USA 91:5918-5921, 1994) revealed a putative predisposing locus to BP through nonparametric methods of linkage analysis. Linkage of ACTHR/MC-2 to BP was not demonstrable under parametric and nonparametric methods of analyses, although affected sib-pair (ASP) method revealed an increase in allele sharing among ill individuals, P = 0.023. Since this receptor is within a potential linkage region, ACTHR/MC-2 could be considered a candidate gene for BP.