Validation of candidate anxiety disorder genes using a carbon dioxide challenge task

• Endophenotypic measures of panic/anxiety may aid in gene identification efforts.
• Carbon dioxide hypersensitivity is a reliable panic/anxiety endophenotype.
• This study tested associations between 11 genes and CO2 hypersensitivity.
• rs1108923 in the ASIC1 gene was associated with baseline respiratory rate.
• No other candidate genes were related to physiological or subjective CO2 response.

Few replicable genetic variants have been identified in the etiology of heritable anxiety disorders such as panic disorder. Endophenotypic measures that have reduced heterogeneity may provide more powerful targets for gene identification. We assessed hypersensitivity to carbon dioxide (a reliable endophenotype of panic and anxiety) in 174 Caucasian college students, who were genotyped on 26 polymorphic markers from 11 genes previously associated with panic/anxiety. Individual trajectories of respiratory and subjective anxiety response to carbon dioxide were measured and tested for association with these genetic markers. One marker in the acid-sensing ion channel 1 (ASIC1) gene, rs1108923, had a significant association with respiratory rate. No genes had a significant association with subjective anxiety response. Our findings support previously reported associations between ASIC1 and panic/anxiety, but not other genes previously associated with anxiety disorders. The use of endophenotypic markers is a promising avenue for gene identification in anxiety and other complex disorders.