CHRNA5 and psychotic disorder: The strongest evidence of a causal effect of tobacco on psychosis is that a genetic locus associated with heaviness of smoking (within the nicotinic receptor CHRNA5-A3-B4 gene cluster) is 1 of the loci most strongly associated with schizophrenia.12 However, this is also theoretically consistent with either confounding by shared genetic effects (biological pleiotropy) or, perhaps less plausibly, reverse causality (ie, biological risk of schizophrenia causing smoking behavior).