rs684513

This cross-population meta-analysis of 32,587 smokers (14,786 European ancestry, 6,889 Asian, 10,912 African American) identified rs16969968 as the only genetic variant in the chromosome 15q25 nicotinic receptor region consistently associated with heavy smoking across all three populations (OR=1.33, 95% CI=1.25-1.42, p=1.1×10⁻¹⁷). Additional variants showed consistent association in European and Asian populations but not African Americans, suggesting rs16969968 is likely a functional causal variant.

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 twin-based genetic association study identified variants in nicotinic acetylcholine receptor genes CHRNA5 and CHRNA3 that significantly increase risk for nicotine dependence. Notably, rs16969968 (CHRNA5, Asp398Asn) and rs1051730 (CHRNA3) showed significant associations with Fagerström Test for Nicotine Dependence scores in two independent samples, while displaying opposite allelic effects for alcohol dependence—a pattern suggesting complex gene-substance interactions. No associations were found with cannabis abuse/dependence.

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.