Genetic linkage to chromosome 4q35 in bipolar affective disorder

Bipolar affective disorder is characterised by severe mood swings (mania and depression) and affects 1-2% of the population. Its complex genetic nature, variable age of onset, and age-specific penetrance confounds linkage studies. No predisposing genes have been identified although a number of groups have mapped susceptibility loci with linkage having been reported to several chromosomes. We have undertaken a two-stage genome screen using 214 microsatellite markers on 87 individuals from the most powerful pedigree in our cohort. The data were analysed by two-point linkage analysis and nonparametric methods under several diagnostic models. Initial lod scores greater than 2 were obtained for four markers although after completion of the second stage, only one marker D4S1652 (θ = 0.15) remained with a lod score of 2.2. Multipoint analysis using additional markers gave a maximum lod score of z = 3.19 between D4S408 and D4S2924. Nonparametric analyses supported our conclusions with a maximum score of 2.61 (P = 0.01) between D4S1652 and D4S171 using Genehunter. Initial analysis of a further 10 pedigrees indicates the presence of the 4q35 locus in at least one additional pedigree. A high density, 1-2 cM map is being constructed using 25 pedigrees (491 individuals, including 115 affected members) to establish a minimal disease haplotype. In summary, our results suggest the presence of an additional susceptibility locus for bipolar disorder on chromosome 4q35.