title: The CHRNA5/A3/B4 gene cluster and tobacco, alcohol, cannabis, inhalants and other substance use initiation: replication and new findings using mixture analyses.
abstract: 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.
authors.affiliation: Department of Psychology, University of Notre Dame, 118 Haggar Hall, Notre Dame, IN 46556, USA. glubke@nd.edu
authors.forename: Gitta H
authors.initials: GH
authors.lastname: Lubke
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Stephens
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Lessem
authors.forename: John K
authors.initials: JK
authors.lastname: Hewitt
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Ehringer
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D019973:Alcohol-Related Disorders / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D058545:Inhalant Abuse / Q000235:genetics; D008297:Male; D002189:Marijuana Abuse / Q000235:genetics; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D019966:Substance-Related Disorders / Q000235:genetics*; D016019:Survival Analysis; D014029:Tobacco Use Disorder / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human