Gene-based analysis suggests association of the nicotinic acetylcholine receptor β1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence

Abstract

Based on our previously identified linkage regions for nicotine dependence (ND), we selected six and five single nucleotide polymorphisms (SNPs) in the muscarinic cholinergic receptor subtype M1 (CHRM1) and nicotinic cholinergic receptor beta1 (CHRNB1), respectively, to determine the association of the two genes with ND in a total of 2,037 subjects from 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP- and/or haplotype-based analyses indicated that the CHRNB1 was significantly associated with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND), in both ethnic samples. The association of rs2302763 in the CHRNB1 was significant with adjusted SQ in the EA sample after correction for multiple testing (P=0.013). Haplotype A-T-A formed by SNPs rs2302765, rs2302762, and rs9217 in the CHRNB1 was significantly associated with the high risk allele for all the three ND measures (minimum P=0.009, 0.006, and 0.008 for SQ, HSI and FTND, respectively) in the AA sample while haplotype A-T-A formed by rs2302765, rs2302763, and rs9217 was significantly positively associated with ND (minimum P=0.005, 0.016, and 0.016 for SQ, HSI and FTND, respectively) in the EA sample. The CHRM1 exhibited significant protective associations of haplotype C-C-A-T-G-G formed by all six SNPs of this gene with at least one ND measure in the AA sample after Bonferroni correction (minimum P=0.008, 0.013, and 0.009 for SQ, HSI and FTND, respectively), but no significant association was found in the EA sample. The significant associations, together with their location of linked region to ND, suggest that the CHRNB1 and CHRM1 are likely candidates for further investigation.

Examination of the Nicotine Dependence (NICSNP) Consortium findings in the Iowa adoption studies population

“…Each of these fi ndings has prior support in the literature: CHRNA2 ( Faraone et al, 2004 ;Sullivan et al, 2004 ), CHRNA7 ( Faraone et al, 2004 ;Greenbaum et al, 2006 ), CHRNB1 ( Lou et al, 2006 ), and CHRNA1 ( Faraone et al, 2004 ). The present fi ndings extend those earlier fi ndings by specifying the haplotypes for each of the loci.…”

Genetics of smoking and depression

“…In humans, variation in a4 is also related to increased smoking quantity and higher scores on one of the most commonly used measures of smoking behavior, the Fagerstrom Test of Nicotine Dependence (FTND; Heatherton et al 1991), in AfricanAmericans, but not in Caucasians . In addition, an association between b1 variation with smoking quantity and FTND has also been observed in AfricanAmericans and Caucasians (Lou et al 2006). Dopamine pathways are a second common target in smoking studies, as these pathways are believed to play important roles in smoking and in substance use disorders more generally (Lessov-Schlaggar et al 2008).…”

Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?

“…CHRNA4, CHRNA5, CHRNA7, CHRNB1, CHRNB2 and CHRNB3), but the functional relevance of the investigated variants in these genes is not yet known. Some evidence for an association with tobacco dependence and smoking status for variants in CHRNA5, CHRNA7, CHRNB1 and CHRNB3 [70][71][72] has been provided. Evidence on the association of variants in the CHRNB2 and CHRNA4 genes is inconclusive [73][74][75][76][77][78].…”