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Sci Rep. 2016 May 10;6:25671. doi: 10.1038/srep25671.

Genetic Relationship between Schizophrenia and Nicotine Dependence.

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Nevada Institute of Personalized Medicine, University of Nevada at Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA.
Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, USA.
Department of Psychiatry Virginia, Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, USA.
Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and VISN4 MIRECC, Philadelphia VA Medical Center, Philadelphia, PA, USA.
Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, and VA CT Healthcare Center, New Haven, CT 06516, USA.
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Department of Biological Psychology, VU University, Amsterdam, Netherlands.
Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, Netherlands.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands.
University of Helsinki, Department of Public Health, P.O.Box 41 (Mannerheimintie 172), 00014 Helsinki, Finland.
National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, P.O. Box 30 (Mannerheimintie 166), 00300 Helsinki, Finland.
University of Helsinki, Institute for Molecular Medicine, P.O. Box 20 (Tukholmankatu 8), 00014 Helsinki, Finland.
UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
Department of Psychology, University of Nevada, Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA.


It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10(-3) and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10(-3) and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity.

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