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Chunk #9 — Discussion — Smoking heaviness phenotype

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Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization.
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We did not use cigarettes per day or smoking cessation SNPs as exposure variables, as we could not stratify these data by smoking status. The SNP that strongly predicts cigarettes per day (rs1051730) does not predict smoking initiation, and only exerts an effect on smoking heaviness after a person has become an established smoker25. The GWAS that identified it was conducted in a sample of daily smokers, unlike that for smoking initiation which was a sample that included ever smokers and never smokers13. This genetic variant has been shown to be associated with schizophrenia risk as a highly correlated SNP (rs8042374) reached genomewide significance in the PGC2 GWAS of schizophrenia12 (used in these analyses), suggesting a possible causal role of smoking heaviness on schizophrenia. However, as the analysis in the current study is based on summary data, we cannot stratify the sample to investigate whether this association is seen in non-smokers (indicating shared genetic aetiology of the two traits) or only in regular smokers (indicating a direct causal association). Whilst this SNP has been identified in unstratified GWAS of outcomes