Localization of bipolar susceptibility locus by molecular genetic analysis of the chromosome 12q23-q24 region in two pedigrees with bipolar disorder and Darier's disease.
OBJECTIVE
The authors previously reported two families (pedigrees 324 and 5501) in which Darier's disease-a rare, autosomal dominant skin disease-and bipolar disorder cosegregate. In each of these families there is complete cosegregation of mood disorder with a segment of chromosome 12q23-q24, consistent with the existence of a highly penetrant dominant variant. Here molecular genetic analyses aimed at localizing and identifying the susceptibility gene in this region are reported.


METHODS
In the two families, the authors undertook 1) linkage and haplotype studies using 45 highly polymorphic molecular genetic markers in order to delineate the region of interest and 2) direct analysis of genes within this region.


RESULTS
Linkage and haplotype information from the most severely affected individuals defined a region of interest that spanned two neighboring regions of 19 megabases (Mb) (D12S362-D12S1646) and 7 Mb (D12S1718-D12S837). Information from all individuals refined the region of interest to 6.5 Mb (D12S127-D12S1646). Systematic study of the coding and flanking intronic regions of 25 known genes within this latter region failed to identify any highly penetrant autosomal dominant disease-conferring mutations in these pedigrees.


CONCLUSIONS
This linkage and haplotype analysis, together with data from several other linkage studies, provides compelling evidence for the existence in the 12q23-q24 region of one or more genes involved in the pathogenesis of bipolar disorder. Further molecular genetic analysis of this region is required to identify the gene(s).
Green
Elaine
E
Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, Wales, UK.
Elvidge
Gareth
G
Jacobsen
Nick
N
Glaser
Beate
B
Jones
Ian
I
O'Donovan
Michael C
MC
Kirov
George
G
Owen
Michael J
MJ
Craddock
Nick
N
D001714:Bipolar Disorder / Q000235:genetics*; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D004252:DNA Mutational Analysis; D007644:Darier Disease / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic
D005819:Genetic Markers