In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment.
In a real data application, we apply our method to the sequencing data from Minnesota Twin Study (MTS) and found potential associations of several nicotine receptor subunit (CHRN) genes, including CHRNB3, associated with nicotine dependence and/or alcohol dependence.
Finally, our meta-analysis of samples with Asian and European origins for five SNPs in CHRNB3 showed significant associations with ND, with p-values ranging from 6.86 × 10<sup>-14</sup> for rs13280604 to 6.50 × 10<sup>-8</sup> for rs4950<sup>.</sup> This represents the first study showing that CHRNB3/A6 are highly associated with ND in a large Chinese Han sample.
Besides the CHRNA4, CHRNB2 and CHRNA5/A3/B4 cluster on chromosome 15, which has been investigated intensively, recent evidence from both genome-wide association studies and candidate gene-based association studies has revealed the crucial roles of the CHRNB3-CHRNA6 gene cluster on chromosome 8 in nicotine dependence (ND).
We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans.
The β3 nicotinic-acetylcholine receptor subunit (encoded by CHRNB3) is depleted in the striatum of PD patients and associated with nicotine dependence.
These results suggest that the CHRNB3-A6 locus contains multiple variants affecting risk for vulnerability to cocaine and nicotine dependence as well as bipolar disorder, suggesting that they have pleiotropic effects.
The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence.
Genome-wide association studies have identified common variation in the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 gene clusters that contribute to nicotine dependence.
The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR) = 0.65, P = 2.4 × 10(-8) ].
Our results suggest that (i) bipolar disorder does not modify the association between nicotine dependence and nicotinic receptor subunit genes, and (ii) variants in CHRNB3/CHRNA6 are independently associated with bipolar disorder.
Here we test the hypothesis that the nicotinic receptor genes CHRNA5 (rs16969968), CHRNA3 (rs578776), CHRNB3 (rs13277254) and CHRND (rs12466358) modify the risk for nicotine dependence associated with peer smoking.
Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence.
We found nominally significant (P<0.05) allelic and genotypic association with smoking initiation of SNP rs2072660 and multilocus haplotypes (P<0.007-0.05) in CHRNB2 and nominal (P<0.05) allelic or genotypic association of SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) with nicotine dependence.