Already, intriguing hints are emerging that larger GWAS are beginning to identify potential environmental or behavioural causes of disease. A recent GWAS led by the Psychiatric Genomics Consortium identified 108 loci associated with schizophrenia [27]. One locus that reached genome-wide significance is located in the CHRNA5-A3-B4 gene cluster on chromosome 15, which, as we have seen, has been consistently shown to contain multiple loci strongly associated with heaviness of smoking [2] among cigarette smokers. There are two possible explanations for this finding. One is that there may be genetic variants in this region that independently influence both heaviness of smoking and schizophrenia risk (i.e., genetic pleiotropy). The other is that this signal captures a causal effect of cigarette smoking on schizophrenia (reflecting a dose–response relationship among the smokers in the study). Again, there is a precedent for this pattern of results: the same region was shown to be associated with lung cancer risk [11], but it is likely that this effect operates entirely via cigarette smoking [13].
