rs6495308

This functional study investigated neurophysiologic effects of genome-wide association study (GWAS)-derived schizophrenia (SCZ) and bipolar disorder (BPD) risk variants in 199 patients with psychotic illness and 74 healthy controls. The SCZ risk allele (G) at TCF4 rs17512836 showed significant association with reduced auditory P3 amplitude (P=0.00017) and delayed P3 latency (P=0.005), suggesting a mechanism involving compromised attention and working memory capacity in psychotic disorders.

This case-control study of 1,025 Chinese males (204 lung cancer cases, 821 controls) examined two SNPs in the CHRNA3-CHRNB4 region (rs6495308 C/T and rs11072768 T/G) on chromosome 15q25. The study found that both variant genotypes were significantly associated with increased smoking behavior (cigarettes per day and pack-years), but after adjustment for smoking intensity, no significant direct association remained between these SNPs and lung cancer risk. The results suggest an indirect effect on lung cancer through smoking behaviors.

This longitudinal study examined three SNPs in the CHRNA5-CHRNA3 nicotinic receptor gene cluster (rs16969968, rs1051703, rs6495308) in 1,301 current smokers from the COMMIT cohort. The A-allele of rs16969968 and rs1051730 were significantly associated with heavy smoking (25+ cigarettes per day, OR=1.21), with AA genotypes showing stronger effects (OR=1.60-1.61). The same variants showed no association with smoking cessation.

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.

This genetic association study examined 505 opioid-dependent patients and found that nicotinic acetylcholine receptor (nAChR) gene variants on chromosome 15q25.1 are associated with both nicotine dependence severity and opioid dependence severity. The CHRNA5 coding variant rs16969968[A] was significantly associated with 1.4-unit higher opioid dependence severity (p < 0.00017), while CHRNA3 variant rs660652[G] was associated with 1.7-fold higher smoking odds and 1.1-unit higher nicotine dependence (p < 0.0007). These findings extend the known role of the 15q25.1 locus from nicotine to prescription opioid dependence phenotypes.

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 comprehensive association study of 226 SNPs across all 16 nicotinic receptor subunit (CHRN) genes identified four distinct genetic loci significantly associated with nicotine dependence in 1050 cases and 879 controls of European descent. The two most significant associations were rs16969968 (CHRNA5, non-synonymous, p=0.00013, OR=1.30) and rs578776 (CHRNA3, p=0.00011, OR=1.34) in the CHRNA5-CHRNA3-CHRNB4 cluster; one locus in the CHRNB3-CHRNA6 cluster tagged by rs13277254 (p=0.00010); and a novel locus in the CHRND-CHRNG cluster tagged by rs12466358 (p=0.00027). Joint analyses confirmed statistical independence of the two CHRNA5-CHRNA3-CHRNB4 signals.

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.