Anxiety and comorbid measures associated with PLXNA2

Context: Reduction in adult neurogenesis has been proposed as a mechanism for onset of depression. Semaphorins and their coreceptors, plexins, have been implicated in nervous system development and in adult neurogenesis. A recent genomewide association study of schizophrenia identified a variant of the gene encoding plexin A2 (PLXNA2) to be most consistently associated across study samples. Common genetic liabilities have been reported between psychiatric and psychological measures, but few examples exist of common genetic variants. Objective: To perform a genetic association study between 6 single nucleotide polymorphisms from the PLXNA2 gene (rs3736963, rs2767565, rs752016, rs1327175, rs2478813, and rs716461) and anxiety, depression, neuroticism, and psychological distress. Design: Extreme discordant and concordant siblings. Setting: Australia. Participants: Study participants were selected with respect to extreme neuroticism scores from a population cohort of 18 742 twin individuals and their siblings. The participants and their parents ( if blood or buccal samples were available) were genotyped, for a total of 2854 genotyped individuals from 990 families. Of these, 624 individuals with a diagnosis of anxiety or depression from 443 families were used in the association analysis. Main Outcome Measures: All the participants completed the Composite International Diagnostic Interview, the 23-item Neuroticism scale of the revised Eysenck Personality Questionnaire, and the 10-item Kessler Psychological Distress Scale. Diagnoses of DSM-IV depression and anxiety were determined from the Composite International Diagnostic Interview. Results: There was evidence of an allelic association between rs2478813 (and other single nucleotide polymorphisms correlated with it) and anxiety, depression, neuroticism, and psychological distress; the association with anxiety is significant after Bonferroni correction for multiple testing (empirical P < .001). The mouse ortholog of PLXNA2 is located in a highly significant linkage region previously reported for anxiety in mice. Conclusion: PLXNA2 is a candidate for causal variation in anxiety and in other psychiatric disorders through its comorbidity with anxiety.