Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at theta = 0.00 (number of families: 36) assuming heterogeneity (alpha = 15%, P = 0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.