Behavior Genetics

, Volume 42, Issue 4, pp 636–646 | Cite as

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

  • Gitta H. LubkeEmail author
  • Sarah H. Stephens
  • Jeffrey M. Lessem
  • John K. Hewitt
  • Marissa A. Ehringer
Original Research


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.


Survival mixture analysis Nicotine initiation Substance use CHRNA5/B3/A4 cluster 



The research of the first author was supported through grant DA018673 by NIDA. ME was supported by AA015336, AA107889, DA026901. SHS was supported by AA007464. JKH and JML were supported by HD031921. This research uses data from Add Health, a program project directed by Kathleen Mullan Harris and designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill, and funded by grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health website (


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Gitta H. Lubke
    • 1
    Email author
  • Sarah H. Stephens
    • 2
  • Jeffrey M. Lessem
    • 3
  • John K. Hewitt
    • 3
    • 4
  • Marissa A. Ehringer
    • 3
    • 5
  1. 1.Department of PsychologyUniversity of Notre DameNotre DameUSA
  2. 2.University of Maryland School of MedicineBoulderUSA
  3. 3.Institute for Behavioral Genetics, University of ColoradoBoulderUSA
  4. 4.Department of Psychology and NeuroscienceUniversity of ColoradoBoulderUSA
  5. 5.Department of Integrative PhysiologyUniversity of ColoradoBoulderUSA

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