There are well-established abnormalities of hypothalamic-pituitary-adrenal (HPA) axis and beta 2 adrenergic receptor function in affective disorders. The genes for the glucocorticoid receptor (GRL) and the beta 2 adrenergic receptor (ADRB2) have been cloned and mapped to distal chromosome 5q. In this study, we have examined polymorphisms of these two candidate genes and other nearby markers for linkage to bipolar disorder in Amish pedigree 110 and three large Icelandic pedigrees. These loci were tested for linkage in two-point and multipoint analyses using a model of autosomal dominant transmission with age-dependent reduced penetrance. Two-point analyses revealed a maximum LOD score of 1.14 at theta = 0.20 from GRL. Linkage could be excluded to ADRB2, as well as to three nearby anonymous markers, D5S207, D5S70, and D5S119. Analyses of another anonymous marker, D5S36, were inconclusive. Multipoint analyses excluded linkage to a 55 cM region including the interval between D5S207 and D5S36 and flanking regions, with the exception of a 7 cM interval between GRL and ADRB2. Despite the intriguing positive LOD score obtained with GRL, linkage to bipolar disorder could not be demonstrated in the region examined.