Association analysis of transcripts from the bipolar susceptibility locus on chromosome 4q35, exclusion of a pathogenic role for eight positional candidate genes

Bipolar affective disorder is a major psychiatric illness with a population prevalence of up to 1.6%. The disorder is genetically complex. To date, no specific gene or DNA sequence variation that predisposes to the disorder has been described, however several susceptibility loci have been proposed through genetic linkage analysis. We previously identified one such susceptibility locus on chromosome 4q35, and refined the interval harboring this susceptibility gene to a size that is amenable to positional cloning. Several independent studies have now been described that support the presence of a susceptibility gene at this locus. In order to identify candidate genes for testing association with bipolar disorder, we previously established a comprehensive transcript map that encompasses the chromosome 4q35 susceptibility locus implicated in our linkage analysis. In this study, we have selected full-length genes from the transcript map and determined the genomic structure of each gene. We identified informative, intragenic single nucleotide polymorphisms (SNPs) by screening all exons and flanking intron sequences in affected individuals from seven bipolar pedigrees that we previously reported as showing evidence for linkage to chromosome 4q35. Analysis of these SNPs was then extended to our unrelated bipolar case-control cohort to test for association with the disorder. Our data suggests that all genes analyzed can be excluded from direct involvement in the disorder. We have therefore, excluded approximately half the genes within the chromosome 4q35 candidate interval from playing a direct pathogenic role in bipolar disorder. (c) 2005 Wiley-Liss, Inc.