• P2RX7;
  • bipolar disorder;
  • major depressive disorder;
  • mood disorders;
  • outcome;
  • neuroticism;
  • anxiety disorders;
  • substance use disorders;
  • mediating effect;
  • moderating effect


We previously reported an association between P2RX7 variant rs208294, diagnosis, and the longitudinal course of mood disorders. Here, we test whether the personality trait neuroticism mediates the effect of P2RX7 on the course of mood disorders.


Patients with DSM-IV mood disorder (256 with major depressive disorder and 168 with bipolar disorder [BD]) were diagnosed with semistructured interviews, genotyped, and followed up for a median of 60 (range 6–83) months. The primary outcome was the prospectively assessed proportion of time spent in any DSM-IV mood episode (time ill). Three types of genetic effect were tested in structural equations models: Model 1: genes directly affect outcome independent of neuroticism, Model 2: neuroticism mediates the effect of genes on outcome, and Model 3: neuroticism and the genetic variant interact in their effect on outcome.


Neuroticism mediated the P2RX7 genetic effect on outcome. The T allele of rs208294 was associated with higher neuroticism, which in turn predicted a higher proportion of time spent in mood episodes (the bootstrap-based test of indirect effect, P = .02). There was no significant interaction between neuroticism and the genotype.


Neuroticism is likely to lie on the causal pathway between the rs208294 T variant and the adverse long-term course of major depressive and BDs. Depression and Anxiety 00:1-8, 2012. © 2012 Wiley Periodicals, Inc.