Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerström test for nicotine dependence

Jennifer Wessel, Sarah M. McDonald, David A. Hinds, Renee P. Stokowski, Harold S. Javitz, Michael Kennemer, Ruth Krasnow, William Dirks, Jill Hardin, Steven J. Pitts, Martha Michel, Lisa Jack, Dennis G. Ballinger, Jennifer B. McClure, Gary E. Swan, Andrew W. Bergen

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53 Scopus citations

Abstract

Common single-nucleotide polymorphisms (SNPs) at nicotinic acetylcholine receptor (nAChR) subunit genes have previously been associated with measures of nicotine dependence. We investigated the contribution of common SNPs and rare single-nucleotide variants (SNVs) in nAChR genes to Fagerström test for nicotine dependence (FTND) scores in treatment-seeking smokers. Exons of 10 genes were resequenced with next-generation sequencing technology in 448 European-American participants of a smoking cessation trial, and CHRNB2 and CHRNA4 were resequenced by Sanger technology to improve sequence coverage. A total of 214 SNP/SNVs were identified, of which 19.2% were excluded from analyses because of reduced completion rate, 73.9% had minor allele frequencies 5%, and 48.1% were novel relative to dbSNP build 129. We tested associations of 173 SNP/SNVs with the FTND score using data obtained from 430 individuals (18 were excluded because of reduced completion rate) using linear regression for common, the cohort allelic sum test and the weighted sum statistic for rare, and the multivariate distance matrix regression method for both common and rare SNP/SNVs. Association testing with common SNPs with adjustment for correlated tests within each gene identified a significant association with two CHRNB2 SNPs, eg, the minor allele of rs2072660 increased the mean FTND score by 0.6 Units (P0.01). We observed a significant evidence for association with the FTND score of common and rare SNP/SNVs at CHRNA5 and CHRNB2, and of rare SNVs at CHRNA4. Both common and/or rare SNP/SNVs from multiple nAChR subunit genes are associated with the FTND score in this sample of treatment-seeking smokers.

Original languageEnglish (US)
Pages (from-to)2392-2402
Number of pages11
JournalNeuropsychopharmacology
Volume35
Issue number12
DOIs
StatePublished - Nov 1 2010

Keywords

  • candidate gene association scan
  • Fagerström test for nicotine dependence
  • single-nucleotide polymorphism
  • treatmentseeking smokers

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    Wessel, J., McDonald, S. M., Hinds, D. A., Stokowski, R. P., Javitz, H. S., Kennemer, M., Krasnow, R., Dirks, W., Hardin, J., Pitts, S. J., Michel, M., Jack, L., Ballinger, D. G., McClure, J. B., Swan, G. E., & Bergen, A. W. (2010). Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerström test for nicotine dependence. Neuropsychopharmacology, 35(12), 2392-2402. https://doi.org/10.1038/npp.2010.120