Panic disorder (PD) is a common anxiety disorder of unknown etiology, with a modest contribution estimated to come from multiple genes. Although pharmacological and behavioral remedies are helpful, PD carries a significant personal and socioecomonic burden in the population. Evidence from basic and pharmaceutical research implicates a number of genes in PD. To date, among many candidate gene studies, only two candidate genes, COMT and ADORA2A, have been established to show significant association and/or linkage to PD in different study populations. Pursuing a convergence of biological, ethological, and pharmaceutical evidence, we investigated genetic variation in previously untested neuropeptide system genes (GRP, GRPR, TACR1, CRHR1), and fine-mapped the PD-linked GABA neurotransmitter receptor genes (GABRB3 and GABRA5), as risk factors for PD in 120 multiplex pedigrees. A second goal was to characterize the heritability of COMT and GABRB3 expression patterns in a control population of nuclear families, in order to identify variants in a ~440-480 kb region around the genes that may contribute to gene function.
We found marginal evidence for association and/or linkage in GRP, TACR1 and CRHR1 that prohibits ruling them out as candidates for PD. Suggestive and significant evidence for linkage and association of PD to GABRB3 and GABRA5 encouraged mutation screens of each gene in a subset of ninety-six probands. A number of potentially functional variants, including a synonymous SNP, 5' and 3' untranslated region SNPs, exon-flanking SNPs, and two mutations that alter transcription factor binding sites were discovered in PD probands. In lymphoblastoid cell lines from Northern European samples represented in the HapMap, variants associated with the heritable expression of GABRB3 were located in introns and 5' to the gene. Significant evidence for heritable COMT expression occurred for variants in genic as well as distant regions, including a gene-poor region ~340 kb from COMT, which was previously linked and associated to PD. This is the first evidence connecting potential long-range regulation of COMT expression to possible COMT dysregulation in PD. As well, nearer upstream and downstream variants to COMT were associated with COMT gene expression, providing new positional targets for putative COMT dysregulation in PD.