Lack of association between the amiloride-sensitive cation channel 2 (ACCN2) gene and anxiety spectrum disorders.
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OBJECTIVE: Ion channels are involved in a wide range of central nervous system functions and have been implicated in several neuropsychiatric disorders. Rodent studies suggest that the acid-sensing ion channel, ASIC1, may play a role in fear conditioning, a model for human anxiety disorders. In this study, we examined, for the first time, the human analog of ASIC1, the amiloride-sensitive cation channel 2 (ACCN2) gene, for its association with genetic risk across a range of anxiety spectrum phenotypes. METHODS: Using multivariate structural equation modeling, we selected twin pairs scoring at the extremes of a latent genetic risk factor that underlies susceptibility to neuroticism, major depression, generalized anxiety disorder, panic disorder, agoraphobia, and social phobia, from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each selected pair for whom DNA was available was entered into a 2-stage, case-control association study for the ACCN2 gene. In the resulting sample of 589 cases and 539 controls, a total of seven single nucleotide polymorphisms that represented the major allelic variation across the ACCN2 locus were screened in stage 1, the positive results of which were tested for replication in stage 2. RESULTS: Although several markers or haplotypic combinations met threshold significance criteria in stage 1, their association was not replicated in stage 2. Post hoc analyses did not reveal significant association to the specific psychiatric phenotypes. CONCLUSIONS: Although the ACCN2 gene may play a role in rodent fear conditioning, we could not detect association with genetic risk shared among human anxiety spectrum disorders.