Catechol O-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder

OBJECTIVE: Genetic epidemiologic and clinical data suggest that comorbid panic disorder may define a subtype of bipolar disorder. Comorbid panic disorder might thereby influence the strength of association between bipolar disorder and genes that have been implicated in bipolar disorder on the basis of their function in monoamine neurotransmission and previously reported linkage results. Polymorphic markers at catechol O-methyltransferase (COMT), serotonin transporter (5-HTT), and tryptophan hydroxylase (TPH) genes were analyzed in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. METHOD: Unrelated subjects of Italian descent meeting DSM-III-R criteria for lifetime bipolar disorder (N=111), with (N=49) or without (N=62) comorbid lifetime panic disorder, were compared to 127 healthy subjects. DNA was extracted from blood leukocytes. The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+218C>A polymorphisms were determined. Genotype and allele frequency comparisons between affected (bipolar disorder, bipolar disorder without panic disorder, or bipolar disorder with panic disorder) and unaffected individuals were carried out with chi-square tests or Fisher's exact tests. RESULTS: Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT Met158 and the short 5-HTTLPR alleles and genotypes. The differences in the frequencies of the TPH IVS7+218A alleles and genotypes approached statistical significance. CONCLUSIONS: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders.