The CHRNA5/A3/B4 Gene Cluster and Tobacco, Alcohol, Cannabis, Inhalants and Other Substance Use Initiation: Replication and New Findings Using Mixture Analyses

Multiple studies have provided evidence for genetic associations between single nucleotide polymorphisms (SNPs) located on the CHRNA5/A3/B4 gene cluster and various phenotypes related to Nicotine Dependence (Greenbaum et al. 2009). Only a few studies have investigated other substances of abuse. The current study has two aims, (1) to extend previous findings by focusing on associations between the CHRNA5/A3/B4 gene cluster and age of initiation of several different substances, and (2) to investigate heterogeneity in age of initiation across the different substances. All analyses were conducted with a subset of the Add Health study with available genetic data. The first aim was met by modeling onset of tobacco, alcohol, cannabis, inhalants, and other substance use using survival mixture analysis (SMA). Ten SNPs in CHRNA5/A3/B4 were used to predict phenotypic differences in the risk of onset, and differences between users and non-users. The survival models aim at investigating differences in the risk of initiation across the 5–18 age range for each phenotype separately. Significant or marginally significant genetic effects were found for all phenotypes. The genetic effects were mainly related to the risk of initiation and to a lesser extent to discriminating between users and non-users. To address the second goal, the survival analyses were complemented by a latent class analysis that modeled all phenotypes jointly. One of the ten SNPs was found to predict differences between the early and late onset classes. Taken together, our study provides evidence for a general role of the CHRNA5/A3/B4 gene cluster in substance use initiation that is not limited to nicotine and alcohol.

[1]  M. Damaj,et al.  Bupropion is a nicotinic antagonist. , 2000, The Journal of pharmacology and experimental therapeutics.

[2]  Matthew C Keller,et al.  A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. , 2011, The American journal of psychiatry.

[3]  Gitta Lubke,et al.  Distinguishing Between Latent Classes and Continuous Factors with Categorical Outcomes: Class Invariance of Parameters of Factor Mixture Models , 2008, Multivariate behavioral research.

[4]  L. Bierut,et al.  Associations and interactions between SNPs in the alcohol metabolizing genes and alcoholism phenotypes in European Americans. , 2009, Alcoholism, clinical and experimental research.

[5]  Jeroen K. Vermunt,et al.  Log-linear event history analysis: A general approach with missing data , 1996 .

[6]  R. Salas,et al.  Influence of Neuronal Nicotinic Receptors over Nicotine Addiction and Withdrawal , 2008, Experimental biology and medicine.

[7]  Scott F. Saccone,et al.  The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. , 2009, Cancer research.

[8]  K. Harris,et al.  The National Longitudinal Study of Adolescent Health (Add Health) Twin Data , 2006, Twin Research and Human Genetics.

[9]  Tatiana Foroud,et al.  Variants in nicotinic receptors and risk for nicotine dependence. , 2008, The American journal of psychiatry.

[10]  F. Ivy Carroll,et al.  Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors , 2006, Molecular Pharmacology.

[11]  B. Lerer,et al.  Role of genetic variants in the CHRNA5–CHRNA3–CHRNB4 cluster in nicotine dependence risk: importance of gene–environment interplay , 2009, Molecular Psychiatry.

[12]  S. D. Glick,et al.  Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener. , 2001, The Alkaloids. Chemistry and biology.

[13]  Daniel F. Gudbjartsson,et al.  A variant associated with nicotine dependence, lung cancer and peripheral arterial disease , 2008, Nature.

[14]  William Wheeler,et al.  Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD , 2010, PLoS genetics.

[15]  Vernell S. Williamson,et al.  Variants in nicotinic acetylcholine receptors α5 and α3 increase risks to nicotine dependence , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[16]  John P. Rice,et al.  Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[17]  S. D. Glick,et al.  Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment , 2003, Pharmacology Biochemistry and Behavior.

[18]  D. Nyholt A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[19]  A. C. Collins,et al.  The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults , 2008, Biological Psychiatry.

[20]  H. Mansvelder,et al.  Bupropion inhibits the cellular effects of nicotine in the ventral tegmental area. , 2007, Biochemical pharmacology.

[21]  M. Neale,et al.  Distinguishing Between Latent Classes and Continuous Factors: Resolution by Maximum Likelihood? , 2006, Multivariate behavioral research.

[22]  M. Biasi,et al.  The α3 and β4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice , 2004, Neuropharmacology.

[23]  J. Cheverud,et al.  A simple correction for multiple comparisons in interval mapping genome scans , 2001, Heredity.

[24]  R. Salas,et al.  Decreased Signs of Nicotine Withdrawal in Mice Null for the β4 Nicotinic Acetylcholine Receptor Subunit , 2004, The Journal of Neuroscience.

[25]  B. Muthén Latent Variable Mixture Modeling , 2001 .

[26]  Michele Zoli,et al.  Structural and functional diversity of native brain neuronal nicotinic receptors. , 2009, Biochemical pharmacology.

[27]  Sarah H. Stephens,et al.  Externalizing Behaviors are Associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster , 2011, Behavior Genetics.

[28]  Isabel R Schlaepfer,et al.  The genetic components of alcohol and nicotine co-addiction: from genes to behavior. , 2008, Current drug abuse reviews.

[29]  C. Gieger,et al.  Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior , 2010, Nature Genetics.

[30]  D. Oslin,et al.  Variation in Nicotinic Acetylcholine Receptor Genes is Associated with Multiple Substance Dependence Phenotypes , 2010, Neuropsychopharmacology.

[31]  Megan E. Piper,et al.  A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction , 2008, PLoS genetics.

[32]  K. Kendler,et al.  Two-part random effects growth modeling to identify risks associated with alcohol and cannabis initiation, initial average use and changes in drug consumption in a sample of adult, male twins. , 2012, Drug and alcohol dependence.

[33]  Bengt Muthén,et al.  Discrete-Time Survival Mixture Analysis , 2005 .

[34]  L. Bierut,et al.  Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking , 2008, Cancer Epidemiology Biomarkers & Prevention.

[35]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[36]  B. Lerer,et al.  Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions , 2009, Molecular Psychiatry.

[37]  B. Muthén,et al.  Deciding on the Number of Classes in Latent Class Analysis and Growth Mixture Modeling: A Monte Carlo Simulation Study , 2007 .

[38]  J. Li,et al.  Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix , 2005, Heredity.

[39]  R. Lukas,et al.  Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. , 1999, The Journal of pharmacology and experimental therapeutics.

[40]  S. Bartlett,et al.  Neuronal nicotinic acetylcholine receptors as pharmacotherapeutic targets for the treatment of alcohol use disorders. , 2010, CNS & neurological disorders drug targets.