rs1948

Family-based association analysis of 22 SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster on chromosome 15 with nicotine dependence in African Americans (N=1053) and European Americans (N=515). Individual SNP analyses showed nominal associations for rs1317286 and rs8040868 in CHRNA3 with smoking quantity and Heaviness Smoking Index (P=0.017–0.05), though none survived correction for multiple testing. Haplotype analysis identified significant associations with nicotine dependence measures before correction in both ethnic groups. Gene-gene interaction analysis using pedigree-based generalized multifactor dimensionality reduction detected significant interactions within CHRNA3 and among all three genes in African Americans and combined samples (P=0.002–0.045).

This Bayesian pharmacogenetic analysis of a bupropion vs placebo smoking cessation trial (n=436 European ancestry participants) identified four SNPs with pharmacogenetic relevance from 59 candidate SNPs in nicotinic acetylcholine receptor genes. The strongest signal was rs871058 in CHRNA5, which showed treatment-by-SNP interaction effects on 7-day smoking cessation rates. Bayesian hypothesis testing proved more conservative than unadjusted frequentist tests but less so than multiplicity-corrected tests, with no control SNPs showing significant associations.

This association study screened 93 SNPs in 19 cholinergic genes (CHAT, CHRM1-5, CHRNA1-7, CHRNA9-10, CHRNB1-4) in two bipolar disorder (BD) pedigree series: NIMH Genetics Initiative (474 samples, 152 families) and Clinical Neurogenetics (83 samples, 22 families). Sib-TDT analysis showed nominally significant association for four SNPs (CHRNA2 rs7017417 P=0.024, CHRNA5 rs514743 P=0.031, CHRNB1 rs2302762 P=0.049, CHRNB4 rs1948 P=0.031), but none reached gene-wide significance after multiple testing correction. The authors conclude that these 19 cholinergic genes are unlikely to play a major role in BD predisposition in these pedigrees.