Genetics of schizophrenia and smoking: An approach to studying their comorbidity based on epidemiological findings

Jose De Leon, Francisco J. Diaz

Research output: Contribution to journalReview articlepeer-review

30 Scopus citations


The association between schizophrenia and tobacco smoking has been described in more than 1,000 articles, many with inadequate methodology. The studies on this association can focus on: (1) current smoking, ever smoking or smoking cessation; (2) non-psychiatric controls or controls with severe mental illness (e.g., bipolar disorder); and (3) higher smoking frequency or greater usage in smokers. The association with the most potential for genetic studies is that between ever daily smoking and schizophrenia; it may reflect a shared genetic vulnerability. To reduce the number of false-positive genes, we propose a three-stage approach derived from epidemiological knowledge. In the first stage, only genetic variations associated with ever daily smoking that are simultaneously significant within the non-psychiatric controls, the bipolar disorder controls and the schizophrenia cases will be selected. Only those genetic variations that are simultaneously significant in the three hypothesis tests will be tested in the second stage, where the prevalence of the genes must be significantly higher in schizophrenia than in bipolar disorder, and significantly higher in bipolar disorder than in controls. The genes simultaneously significant in the second stage will be included in a third stage where the gene variations must be significantly more frequent in schizophrenia patients who did not start smoking daily until their 20s (late start) versus those who had an early start. Any genetic approach to psychiatric disorders may fail if attention is not given to comorbidity and epidemiological studies that suggest which comorbidities are likely to be explained by genetics and which are not. Our approach, which examines the results of epidemiological studies on comorbidities and then looks for genes that simultaneously satisfy epidemiologically suggested sets of hypotheses, may also apply to the study of other major illnesses.

Original languageEnglish
Pages (from-to)877-901
Number of pages25
JournalHuman Genetics
Issue number6
StatePublished - Jun 2012

Bibliographical note

Funding Information:
Acknowledgments F. Diaz, Ph.D. was partly supported by an NIH Institutional Clinical and Translational Science Award to the University of Kansas Medical Center (1ULRR033179, R033177, RR033178). No commercial organizations had any role in the writing of this paper for publication. The authors acknowledge Lorraine Maw, M.A., and Margaret T. Susce, R.N., M.L.T., at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, who helped in editing the article and managing the large number of articles reviewed. The authors are grateful to the reviewers who helped them to clarify issues and improve the article.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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