Isolation of chromosome 18-specific brain transcripts as positional candidates for bipolar disorder.

Several studies have proposed the existence of susceptibility loci for bipolar disorder on chromosome 18. To identify possible candidate genes for this disease, we isolated brain-expressed transcripts by direct cDNA selection on chromosome 18-specific biotinylated cosmid clones. Longer cognate cDNA clones of the selected cDNAs were isolated from a normalized infant brain cDNA library. Physical mapping by PCR on a panel of somatic cell hybrids was conducted by the use of primers derived from partial sequences on either the 5' or 3' ends of the clones. In our initial analysis, 48 cDNA clones were found to be chromosome 18-specific, mapping to different subchromosomal regions. Sequence redundancy among these clones yielded 30 unique transcripts, five of which were represented in previously known genes. Further sequencing of the remaining 25 unique cDNA clones confirmed the absence of significant homology to known genes, indicating that these transcripts represented novel genes. Mapping with the use of a radiation hybrid panel positioned the brain cDNAs to within = 100 to 1100 kb from reference sequence tag sites (STSs) and assembled them into six high resolution linkage groups. The majority of the transcripts were found to cluster to discrete locations on 18p and 18q, previously hypothesized as susceptibility regions for bipolar disorder, identifying them as positional candidate genes.