Abstract
Schizophrenia shows a genetic correlation with both anxiety disorder and neuroticism, a trait strongly associated with anxiety. However, genetic correlations do not discern causality from genetic confounding. We therefore aimed to investigate whether anxiety-related phenotypes lie on the causal pathway to schizophrenia using Mendelian randomization (MR). Four MR methods, each with different assumptions regarding instrument validity, were used to investigate casual associations of anxiety and neuroticism related phenotypes on schizophrenia, and vice versa: inverse variance weighted (IVW), weighted median, weighted mode, and, when appropriate, MR Egger regression. MR provided evidence of a causal effect of neuroticism on schizophrenia (IVW odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.12-1.59), but only weak evidence of a causal effect of anxiety on schizophrenia (IVW OR: 1.10, 95% CI: 1.01-1.19). There was also evidence of a causal association from schizophrenia liability to anxiety disorder (IVW OR: 1.28, 95% CI: 1.18-1.39) and worry (IVW beta: 0.05, 95% CI: 0.03-0.07), but effect estimates from schizophrenia to neuroticism were inconsistent in the main analysis. The evidence of neuroticism increasing schizophrenia risk provided by our results supports future efforts to evaluate neuroticism- or anxiety-based therapies to prevent onset of psychotic disorders.
Highlights
Schizophrenia is a heritable psychotic disorder characterized by positive and negative symptoms
Across all Mendelian randomization (MR) approaches, estimated effect sizes were in the direction of a causal association between anxiety disorder and schizophrenia; the confidence intervals (CIs) often included protective effects
In sensitivity analyses omitting loci correlated between neuroticism and schizophrenia phenotypes, results were similar to primary analyses with no strong evidence of effect of higher genetic liability to schizophrenia leading to changes in levels of neuroticism or depressed affect, though the directions of the effect estimates were consistent, but strong evidence that genetic liability to schizophrenia is associated to higher levels of worry (Table 4, Figure S5d–f)
Summary
Schizophrenia is a heritable psychotic disorder characterized by positive (e.g., hallucinations and delusions) and negative (e.g., apathy and flattened affect) symptoms It is associated with significant health, social and financial burden (Chong et al, 2016). The core assumptions of MR are i) the genetic instrumental variables must be associated with the risk factor of interest, ii) they share no common cause with the outcome (i.e., are independent of confounders), and iii) they only affect the outcome through the risk factor (the exclusion restriction assumption). If these assumptions are met, this approach can overcome issues of reverse causation and unmeasured confounding. We aimed to examine whether anxiety or neuroticism have a causal effect on schizophrenia using a two-sample MR study design
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