title: Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization.
abstract: Smoking is strongly associated with schizophrenia. Although it has been widely assumed that this reflects self-medication, recent studies suggest that smoking may be a risk factor for schizophrenia. We performed two-sample bi-directional Mendelian randomization using summary level genomewide association data from the Tobacco And Genetics Consortium and Psychiatric Genomics Consortium. Variants associated with smoking initiation and schizophrenia were combined using an inverse-variance weighted fixed-effects approach. We found evidence consistent with a causal effect of smoking initiation on schizophrenia risk (OR 1.73, 95% CI 1.30-2.25, p < 0.001). However, after relaxing the p-value threshold to include variants from more than one gene and minimize the potential impact of pleiotropy, the association was attenuated (OR 1.03, 95% CI 0.97-1.09, p = 0.32). There was little evidence in support of a causal effect of schizophrenia on smoking initiation (OR 1.01, 95% CI 0.98-1.04, p = 0.32). MR Egger regression sensitivity analysis indicated no evidence for pleiotropy in the effect of schizophrenia on smoking initiation (intercept OR 1.01, 95% CI 0.99-1.02, p = 0.49). Our findings provide little evidence of a causal association between smoking initiation and schizophrenia, in either direction. However, we cannot rule out a causal effect of smoking on schizophrenia related to heavier, lifetime exposure, rather than initiation.
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
authors.forename: Suzanne H
authors.initials: SH
authors.lastname: Gage
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Jones
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Taylor
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Burgess
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: Stanley
authors.initials: S
authors.lastname: Zammit
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.|UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Munafò
mesh_terms: D004198:Disease Susceptibility; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods; D016017:Odds Ratio; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology* / Q000209:etiology*; D012907:Smoking / Q000009:adverse effects*