CHRNA5-A3-B4 were associated with increased schizophrenia risk (Ripke et al., 2014). These variants are known to be strongly associated with heaviness of smoking (Munafò et al., 2012; Thorgeirsson et al., 2008; Tobacco Consortium, 2010; Ware, van den Bree, & Munafò, 2011). Therefore, one interpretation is a possible causal effect of smoking on schizophrenia (Gage & Munafò, 2015). Furthermore, there is evidence of genetic correlations between smoking, schizophrenia and depression (Hartz et al., 2018; Liu et al., 2019) warranting further investigation of possible causal effects. Prospective observational studies using related individuals to control for genetic and environmental confounding have suggested a dose–response effect of smoking on schizophrenia (Kendler, Lönn, Sundquist, & Sundquist, 2015) and depression (Kendler et al., 1993). Meta-analyses show further evidence for an increased relative risk of schizophrenia in smokers over non-smokers (Gurillo, Jauhar, Murray, & MacCabe, 2015; Scott et al., 2018) and a reduction in depressive symptoms following smoking cessation (Taylor, McNeill et al., 2014). Although these studies suggest a potential causal effect, more robust methods are required to triangulate evidence and allow for stronger causal inference (Munafò & Davey Smith, 2018).
