rs16969968

This meta-analysis using GWAS summary statistics examined genetic correlations between smoking behaviors (cigarettes smoked per day, smoking cessation), lung cancer, and COPD. Strong positive genetic correlations were found between heavier smoking, reduced smoking cessation, and increased lung cancer and COPD risk. Notably, rs56113850 in CYP2A6 (effect allele C) showed a paradoxical pattern: associated with heavier smoking (z=19.2, p=1.10×10⁻⁸¹) and lung cancer (z=8.91, p=5.02×10⁻¹⁹) yet also with increased smoking cessation (z=-8.17, p=2.52×10⁻²⁶), highlighting the complex relationship between nicotine metabolism and smoking behaviors.

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.

Association study of 55 SNPs in 887 Hungarian adults examining genetic predisposition to aggression measured by the Buss-Perry Aggression Questionnaire. The HTR2A rs7322347 intronic variant showed significant association with aggression after Bonferroni correction (p = 0.0007), with carriers of the minor A allele showing lower aggression levels. The DRD4 rs916455 variant also showed nominal significance (p = 0.0275) but did not survive multiple testing correction.

A bivariate Mann-Whitney (BMW) approach was developed to identify genetic variants and interactions contributing to nicotine dependence (ND) and alcohol dependence (AD) comorbidity. Analysis of 184 known AD and ND SNPs in the SAGE dataset identified rs16969968 in CHRNA5 associated with both AD and ND in Caucasian samples (P = 8.23 × 10⁻³ in COGA, P = 1.06 × 10⁻³ in FSCD). The GG genotype showed increased risk for both conditions, with odds ratios of 0.678 (95% CI: 0.501-0.919) for comorbidity in COGA.

This methodological paper presents an approach to interpret joint SNP analysis results by determining whether two apparently distinct genetic signals could actually be produced by a single underlying causal variant. The authors applied this method to joint analysis of rs16969968 and rs588765 in CHRNA5 for nicotine dependence (COGEND sample, n=2053), finding no evidence that a single third SNP could fully explain the observed associations. The method demonstrates that causal variants need not be highly correlated with observed signals nor have large effect sizes to produce joint SNP results.

This pharmacogenetic study of 52 healthy nonsmoking volunteers demonstrates that the effect of nicotine on prepulse inhibition (a measure of sensorimotor gating) is modulated by the CHRNA3 rs1051730 polymorphism. Nicotine significantly enhanced PPI in TT homozygotes (p=0.03) but tended to worsen PPI in TC and CC carriers (p=0.16-0.28). The findings suggest that individuals carrying the nicotine dependence risk allele (T allele) may be more susceptible to neurocognitive enhancement from nicotine, potentially contributing to addiction vulnerability.

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 paper introduces the Forward U-Test, a statistical method for detecting gene-gene interactions affecting quantitative traits. Applied to nicotine dependence in the SAGE dataset, the method identified two SNPs with significant joint association: rs16969968 (CHRNA5) and rs1122530 (NTRK2), with a p-value of 5.31e-7 in the discovery cohort (FSCD) and replication p-values of 1.08e-5 (COGA) and 0.02 (COGEND), demonstrating an essential interaction effect between the two loci.

This PhD thesis comprehensively explores associations between the CHRNA5-A3-B4 nicotinic acetylcholine receptor gene cluster and smoking-related behaviors. Using systematic review/meta-analysis, genetic epidemiology, laboratory-based techniques, and genome-wide meta-analysis, the study found compelling evidence for a small, robust association between rs16969968/rs1051730 and daily cigarette consumption with a per-allele effect of approximately one cigarette per day (beta≈1.0). A genome-wide meta-analysis of cotinine levels in 2,139 current smokers identified multiple variants in the CHRNA5 region strongly associated with tobacco exposure. However, no association was observed with smoking initiation in a prospectively-assessed cohort.

A case-control study of 505 lung cancer patients and 498 controls from a Chinese population investigated CHRNA5 gene variants in the promoter region. Two haplotype combinations at positions -1640 (rs3829787, C/T) and -62 (rs3841324, ins/del) showed protective effects: the T/ins haplotype (OR=0.33, p=0.0002) and C/del haplotype (OR=0.61, p=0.0094) were significantly associated with reduced lung cancer susceptibility. Functional studies revealed these protective haplotypes had opposite promoter activities, with T/ins showing highest activity and C/del showing lowest activity, suggesting both hyperactivity and hypoactivity of the CHRNA5 promoter may reduce cancer risk.

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 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.

A genome-wide association study of 7,188 Caucasian individuals examined the genetic basis of behavioral disinhibition across five phenotypes (nicotine use, alcohol consumption, alcohol dependence, illicit drug use, and non-substance disinhibition) using 527,829 autosomal SNPs. While no variants reached genome-wide significance after multiple testing correction, rs1868152 showed association with illicit drug use (p = 4.9 × 10⁻⁸, beta = 15.68) and 13 additional SNPs showed consistent directional effects across multiple phenotypes. Biometric heritability estimates (49-70%) substantially exceeded GCTA common variant estimates (8-37%), indicating that much of the genetic architecture remains unaccounted for by common variants.

This population-based study examined natural selection on nicotinic receptor gene clusters (CHRNB3-A6 on chromosome 8 and CHRNA5-A3-B4 on chromosome 15) using 1000 Genomes data from three populations. Using Tajima's D and integrated haplotype score (iHS) tests, the authors found strong evidence for positive selection in the CHRNB3-A6 region and moderate evidence in CHRNA5-A3-B4. These regions harbor variants previously associated with nicotine dependence (rs16969968, rs1451240) and cocaine dependence. To understand the target of selection, the authors tested variants in COGA subjects (N=492) for association with cognitive phenotypes (WAIS tests) and found one significant association: rs7017612 with WAIS Digit Symbol score (β=0.43, p=0.003), suggesting memory and learning may be the driving force behind selection.

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 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.