Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence

Helen Marie Kamens, Robin P. Corley, Phillip A. Richmond, Todd M. Darlington, Robin Dowell, Christian J. Hopfer, Michael C. Stallings, John K. Hewitt, Sandra A. Brown, Marissa A. Ehringer

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    Common SNPs in nicotinic acetylcholine receptor genes (CHRN genes) have been associated with drug behaviors and personality traits, but the influence of rare genetic variants is not well characterized. The goal of this project was to identify novel rare variants in CHRN genes in the Center for Antisocial Drug Dependence (CADD) and Genetics of Antisocial Drug Dependence (GADD) samples and to determine if low frequency variants are associated with antisocial drug dependence. Two samples of 114 and 200 individuals were selected using a case/control design including the tails of the phenotypic distribution of antisocial drug dependence. The capture, sequencing, and analysis of all variants in 16 CHRN genes (CHRNA1-7, 9, 10, CHRNB1-4, CHRND, CHRNG, CHRNE) were performed independently for each subject in each sample. Sequencing reads were aligned to the human reference sequence using BWA prior to variant calling with the Genome Analysis ToolKit (GATK). Low frequency variants (minor allele frequency < 0.05) were analyzed using SKAT-O and C-alpha to examine the distribution of rare variants among cases and controls. In our larger sample, the region containing the CHRNA6/CHRNB3 gene cluster was significantly associated with disease status using both SKAT-O and C-alpha (unadjusted p values <0.05). More low frequency variants in the CHRNA6/CHRNB3 gene region were observed in cases compared to controls. These data support a role for genetic variants in CHRN genes and antisocial drug behaviors.

    Original languageEnglish (US)
    Pages (from-to)693-704
    Number of pages12
    JournalBehavior Genetics
    Volume46
    Issue number5
    DOIs
    StatePublished - Sep 1 2016

    Fingerprint

    drug abuse
    Substance-Related Disorders
    drug
    gene
    Genes
    genes
    sampling
    drugs
    cholinergic receptors
    Nicotinic Receptors
    Multigene Family
    multigene family
    Gene Frequency
    Pharmaceutical Preparations
    gene frequency
    Single Nucleotide Polymorphism
    Personality
    Tail
    tail
    Genome

    All Science Journal Classification (ASJC) codes

    • Ecology, Evolution, Behavior and Systematics
    • Genetics
    • Genetics(clinical)

    Cite this

    Kamens, H. M., Corley, R. P., Richmond, P. A., Darlington, T. M., Dowell, R., Hopfer, C. J., ... Ehringer, M. A. (2016). Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence. Behavior Genetics, 46(5), 693-704. https://doi.org/10.1007/s10519-016-9792-4
    Kamens, Helen Marie ; Corley, Robin P. ; Richmond, Phillip A. ; Darlington, Todd M. ; Dowell, Robin ; Hopfer, Christian J. ; Stallings, Michael C. ; Hewitt, John K. ; Brown, Sandra A. ; Ehringer, Marissa A. / Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence. In: Behavior Genetics. 2016 ; Vol. 46, No. 5. pp. 693-704.
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    abstract = "Common SNPs in nicotinic acetylcholine receptor genes (CHRN genes) have been associated with drug behaviors and personality traits, but the influence of rare genetic variants is not well characterized. The goal of this project was to identify novel rare variants in CHRN genes in the Center for Antisocial Drug Dependence (CADD) and Genetics of Antisocial Drug Dependence (GADD) samples and to determine if low frequency variants are associated with antisocial drug dependence. Two samples of 114 and 200 individuals were selected using a case/control design including the tails of the phenotypic distribution of antisocial drug dependence. The capture, sequencing, and analysis of all variants in 16 CHRN genes (CHRNA1-7, 9, 10, CHRNB1-4, CHRND, CHRNG, CHRNE) were performed independently for each subject in each sample. Sequencing reads were aligned to the human reference sequence using BWA prior to variant calling with the Genome Analysis ToolKit (GATK). Low frequency variants (minor allele frequency < 0.05) were analyzed using SKAT-O and C-alpha to examine the distribution of rare variants among cases and controls. In our larger sample, the region containing the CHRNA6/CHRNB3 gene cluster was significantly associated with disease status using both SKAT-O and C-alpha (unadjusted p values <0.05). More low frequency variants in the CHRNA6/CHRNB3 gene region were observed in cases compared to controls. These data support a role for genetic variants in CHRN genes and antisocial drug behaviors.",
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    Kamens, HM, Corley, RP, Richmond, PA, Darlington, TM, Dowell, R, Hopfer, CJ, Stallings, MC, Hewitt, JK, Brown, SA & Ehringer, MA 2016, 'Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence', Behavior Genetics, vol. 46, no. 5, pp. 693-704. https://doi.org/10.1007/s10519-016-9792-4

    Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence. / Kamens, Helen Marie; Corley, Robin P.; Richmond, Phillip A.; Darlington, Todd M.; Dowell, Robin; Hopfer, Christian J.; Stallings, Michael C.; Hewitt, John K.; Brown, Sandra A.; Ehringer, Marissa A.

    In: Behavior Genetics, Vol. 46, No. 5, 01.09.2016, p. 693-704.

    Research output: Contribution to journalArticle

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    AU - Dowell, Robin

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