C Smyth

Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q

Objective To localize genes conferring susceptibility to bipolar affective disorder. Methods Seven families were selected on the basis of containing multiple cases of bipolar affective disorder present in three or more generations, an absence of schizophrenia and unilineal transmission. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10 cM intervals across the whole genome. All markers were subjected to initial two‐point and three‐point analyses using LOD score and model‐free analysis. All regions producing a result significant at P<0.01 were then subjected to four‐point LOD score analysis under the assumption of heterogeneity. Results A four‐point LOD score of 2.8 was obtained using a dominant model and including unipolar cases as affected in the region of D12S342. Four‐point LOD scores of 2 were obtained around D1S243, D1S251 and D3S1265. The positive results around D1S243 were accounted for by a LOD score of 3.1 occurring in a single pedigree. Conclusions Since there has been previous strong support for linkage to the region of 12q23‐q24 around D12S342, it now seems very probable that it does indeed contain a gene influencing susceptibility to bipolar affective disorder. Some evidence for linkage in the region of 1q near to D1S251 has been reported in one previous study. It therefore seems that this region of 1q and the region of 1p close to D1S243 may also harbour susceptibility genes.

Linkage Analysis of Manic Depression (Bipolar Affective Disorder) in Icelandic and British Kindreds using Markers on the Short Arm of Chromosome 18

Attempts were made to follow up results of a previous linkage study which suggested that a locus-modifying susceptibility to bipolar and related unipolar affective disorder might be present in the pericentromeric region of the short arm of chromosome 18. Twenty-three multiply affected pedigrees collected from Iceland and the UK were genotyped using three highly polymorphic microsatellite markers at D18S37, D18S40 and D18S44 which span the region implicated. Lod score analyses under the assumption of heterogeneity and non-parametric linkage analyses were performed. The total lod scores obtained were strongly negative, and analysis allowing for heterogeneity did not suggest that any subgroup of the families was linked. Model-free linkage analysis using extended relative pair analysis and MFLINK also failed to detect any evidence for linkage. Our study provides no support for the presence of a locus-modifying genetic susceptibility to bipolar affective disorder in the pericentromeric region of chromosome 18q11. Further analyses in independent samples should help to reveal whether our negative results are due to locus heterogeneity or whether the original results were false-positive.

Adjacent genetic markers on chromosome 11p15.5 at or near the tyrosine hydroxylase locus that show population linkage disequilibrium with each other do not show allelic association with bipolar affective disorder.

BACKGROUND Linkage and association studies have suggested genetic susceptibility to bipolar affective disorder in a region of chromosome 11 around the tyrosine hydroxylase locus. We attempted to test the hypothesis that there was allelic association between polymorphisms around the tyrosine hydroxylase locus and bipolar affective disorder. METHODS A case-control association study was employed using four polymorphic markers, which span a region of approximately 2 cM across the tyrosine hydroxylase locus. RESULTS No evidence for allelic association between bipolar affective disorder and any of these markers was found. However, linkage disequilibrium between the markers was detected. CONCLUSIONS This finding diminishes the probability that genes in this region influence susceptibility to bipolar affective disorder, at least in our sample.