• Kenneth S Kendler, Sara Larsson Lönn, Jan Sundquist, and Kristina Sundquist.
• From the Virginia Institute for Psychiatric and Behavioral Genetics, the Department of Psychiatry, and the Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond; the Center for Primary Health Care Research, Lund University, Malmö, Sweden; and the Stanford Prevention Research Center, Stanford University School of Medicine, Stanford.
• Am J Psychiatry. 2015 Nov 1; 172 (11): 1092-100.

ObjectiveThe purpose of this study was to clarify the causes of the smoking-schizophrenia association.MethodUsing Cox proportional hazard and co-relative control models, the authors predicted future risk for a diagnosis of schizophrenia or nonaffective psychosis from the smoking status of 1,413,849 women and 233,879 men from, respectively, the Swedish birth and conscript registries.ResultsSmoking was assessed in women at a mean age of 27 and in men at a mean age of 18. The mean age at end of follow-up was 46 for women and 26 for men. Hazard ratios for first-onset schizophrenia were elevated both for light smoking (2.21 [95% CI=1.90-2.56] for women and 2.15 [95% CI=1.25-3.44] for men) and heavy smoking (3.45 [95% CI=2.95-4.03] for women and 3.80 [95% CI=1.19-6.60] for men). These associations did not decline when schizophrenia onsets 3-5 years after smoking assessment were censored. When age, socioeconomic status, and drug abuse were controlled for, hazard ratios declined only modestly in both samples. Women who smoked into late pregnancy had a much higher risk for schizophrenia than those who quit early. Hazard ratios predicting nonaffective psychosis in the general population, in cousins, in half siblings, and in full siblings discordant for heavy smoking were, respectively, 2.67, 2.71, 2.54, and 2.18. A model utilizing all relative pairs predicted a hazard ratio of 1.69 (95% CI=1.17-2.44) for nonaffective psychosis in the heavy-smoking member of discordant monozygotic twin pairs.ConclusionsSmoking prospectively predicts risk for schizophrenia. This association does not arise from smoking onset during a schizophrenic prodrome and demonstrates a clear dose-response relationship. While little of this association is explained by epidemiological confounders, a portion arises from common familial/genetic risk factors. However, in full siblings and especially monozygotic twins discordant for smoking, risk for nonaffective psychosis is appreciably higher in the smoking member. These results can help in evaluating the plausibility of various etiological hypotheses for the smoking-schizophrenia association.

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