Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod = 1.76, theta = 0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P < 0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall = 2.32, P = 0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod = 2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22. (C) 2004 Lippincott Williams Wilkins.