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A protocadherin gene cluster regulatory variant is associated with nicotine withdrawal and the urge to smoke

Molecular Psychiatry volume 22, pages 242–249 (2017)Cite this article

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Abstract

Nicotine withdrawal symptoms contribute to relapse in smokers, thereby prolonging the harm caused by smoking. To investigate the molecular basis for this phenomenon, we conducted a genome-wide association study of DSM-IV nicotine withdrawal in a sample of African American (AA) and European American (EA) smokers. A combined AA and EA meta-analysis (n=8021) identified three highly correlated single nucleotide polymorphisms (SNPs) in the protocadherin (PCDH)-α, -β and -γ gene cluster on chromosome 5 that were associated with nicotine withdrawal (P<5 × 10−8). We then studied one of the SNPs, rs31746, in an independent sample of smokers who participated in an intravenous nicotine infusion study that followed overnight smoking abstinence. After nicotine infusion, abstinent smokers with the withdrawal risk allele experienced greater alleviation of their urges to smoke, as assessed by the Brief Questionnaire on Smoking Urges (BQSU). Prior work has shown that the PCDH-α, -β and -γ genes are expressed in neurons in a highly organized manner. We found that rs31746 mapped to a long-range neuron-specific enhancer element shown previously to regulate PCDH-α, -β and -γ gene expression. Using Braincloud mRNA expression data, we identified a robust and specific association between rs31746 and PCDH-β8 mRNA expression in frontal cortex tissue (P<1 × 10−5). We conclude that PCDH-α, -β and -γ gene cluster regulatory variation influences the severity of nicotine withdrawal. Further studies on the PCDH-α, -β and -γ genes and their role in nicotine withdrawal may inform the development of novel smoking cessation treatments and reduce the harm caused by tobacco smoking.

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Acknowledgements

This research was supported by the Veterans Administration (VA) Mental Illness Research, Education and Clinical Center (MIRECC) and a VA VISN1 Career Development Award; NIH grants R03 DA027474, R01 AA017535, R01 DA030976, R01 DA12690, MSTP 5T32GM007205-38, CTSA 8UL1TR000142 TL1, F30 DA037665; and Army STARRS, which is sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The Yale Biomedical Supercomputer, funded by NIH/NCRR (1 S10 RR19895-01), was used for some analyses. The publically available datasets used for the analyses described in this manuscript were obtained from dbGaP (accession number phs000092.v1.p and phs000417.v2.p1). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning and with general study coordination was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C).

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    K P Jensen, A H Smith, A I Herman, M Sofuoglu & J Gelernter

  2. VA Connecticut Healthcare System, West Haven, CT, USA

    K P Jensen, A H Smith, A I Herman, M Sofuoglu & J Gelernter

  3. Interdepartmental Neuroscience Program and Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA

    A H Smith

  4. Department of Medicine (Biomedical Genetics), Boston University School of Medicine and Public Health, Boston, MA, USA

    L A Farrer

  5. Department of Neurology, Boston University School of Medicine and Public Health, Boston, MA, USA

    L A Farrer

  6. Department of Ophthalmology, Boston University School of Medicine and Public Health, Boston, MA, USA

    L A Farrer

  7. Department of Epidemiology, Boston University School of Medicine and Public Health, Boston, MA, USA

    L A Farrer

  8. Department of Biostatistics, Boston University School of Medicine and Public Health, Boston, MA, USA

    L A Farrer

  9. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and the VISN4 MIRECC, Philadelphia VA Medical Center, Philadelphia, PA, USA

    H R Kranzler

  10. Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA

    J Gelernter

  11. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    J Gelernter

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  1. K P Jensen
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Competing interests

Dr Sofuoglu has served as an expert witness on behalf of Pfizer in lawsuits related to varenicline. Dr Kranzler has served as a consultant or advisory board member for Alkermes, Indivior, Lundbeck and Otsuka. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck and Pfizer. The remaining authors declare no biomedical financial interests or potential conflicts of interest.

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Jensen, K., Smith, A., Herman, A. et al. A protocadherin gene cluster regulatory variant is associated with nicotine withdrawal and the urge to smoke. Mol Psychiatry 22, 242–249 (2017). https://doi.org/10.1038/mp.2016.43

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