A SUSCEPTIBILITY LOCUS FOR BIPOLAR AFFECTIVE-DISORDER ON CHROMOSOME 4Q35

Bipolar affective disorder (BAD) affects similar to 1% of the populati on and shows strong heritability. To identify potential BAD susceptibi lity loci, we undertook a 15-cM genome screen, using 214 microsatellit e markers on the 35 most informative individuals of a large, statistic ally powerful pedigree. Data were analyzed by parametric two-point lin kage methods under several diagnostic models. LOD scores >1.00 were ob tained for 21 markers, with four of these >2.00 for at least one model . The remaining 52 individuals in the family were genotyped with these four markers, and LOD scores remained positive for three markers. A m ore intensive screen was undertaken in these regions, with the most po sitive results being obtained for chromosome 4q35. Using a dominant mo del of inheritance with 90% maximum age-specific penetrance and includ ing bipolar I, II, schizoaffective/mania, and unipolar individuals as affected, we obtained a maximum two-point LOD score of 2.20 (theta = . 15) at D4S1652 and a maximum three-point LOD score of 3.19 between D4S 408 and D4S2924. Nonparametric analyses further supported the presence of a locus on chromosome 4q35. A maximum score of 2.62 (P = .01) was obtained between D4S1652 and D4S171 by use of the GENEHUNTER program, and a maximum score of 3.57 (P = .0002) was obtained at D4S2924 using the affected pedigree member method. Analysis of a further IO pedigree s suggests the presence of this locus in at least one additional famil y, indicating a possible predisposing locus and not a pedigree-specifi c mutation. Our results suggest the presence of a novel BAD susceptibi lity locus on chromosome 4q35.