Semaphorin receptor gene, PLXNA2: a common causal variant for a spectrum of psychiatric disorders?
Common genetic liabilities exist between schizophrenia, depression and measures of personality, but few examples of specific common genetic variants exist. A recent genome-wide association study for schizophrenia (Mah et al, 2006, Mol Psychiatry) identified a variant of the gene encoding plexin A2 (PLXNA2) to be most consistently associated across discovery and replication samples. Plexins are members of the semaphorin receptor family, which together with neuropilins mediate the effect of semaphorins, which have been implicated in the development (particularly axonal guidance) and maintenance of the nervous system. A genetic association study was conducted between six SNPs from the PLXNA2 gene and measures of depression, anxiety, personality and psychological distress. The study sample consisted of 1834 people selected as concordant or discordant sibling pairs with respect to extreme Eysenck Personality Questionnaire (EPQ) neuroticism scores from a population sample of 18,742 Australian twin individuals and their siblings. Study participants completed detailed Composite International Diagnostic Interview (CIDI) and EPQ personality and Kessler Psychological Distress questionnaires, resulting in measures of all phenotypes on all individuals. Significant association was found between multiple individual SNPs and their haplotypes and both anxiety and depression phenotypes. For example, the pedigree disequilibrium association test p of SNP rs2478813 with any DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) anxiety diagnosis was 0.0013 and with any DSM-IV depression diagnosis was 0.024. Uniquely, the study group allows us to investigate the phenotypic sub-groups that drive the observed associations and the relationships between them. Our results suggest that PLXNA2 may be a common causal variant for a spectrum of psychiatric disorders.