A Mendelian randomization study of the causal association between anxiety phenotypes and schizophrenia

Hannah J Jones*, David Martin, Sarah J Lewis, George Davey Smith, Michael C O'Donovan, Michael John Owen, James T R Walters, Stanley Zammit

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

6 Citations (Scopus)
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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.
Original languageEnglish
Number of pages10
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Early online date24 Jun 2020
Publication statusE-pub ahead of print - 24 Jun 2020


  • schizophrenia
  • anxiety
  • neuroticism
  • Mendelian randomization


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