rs1051730

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 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 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 mediation analysis study of 3,424 COPD cases and 1,872 controls examined direct and indirect genetic effects of known COPD susceptibility loci. The AGPHD1/CHRNA3 variants (rs1051730, rs8034191) showed ~30% of their total effect on COPD mediated by pack-years smoking (OR 1.256-1.305), while IREB2 (rs13180) showed no significant smoking-mediated effect, suggesting independent pathways. FAM13A (rs7671167) and HHIP (rs13118928) demonstrated direct effects on COPD independent of smoking.

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 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.

This paper applies a bias correction method for odds ratio estimates from GWAS discovery data, demonstrating that the 'winner's curse' affects initial effect size estimates. The authors applied conditional maximum likelihood estimation to correct bias in GWAS findings from multiple complex diseases (breast cancer, colorectal cancer, lung cancer, prostate cancer, type I and II diabetes) and show that bias-adjusted odds ratios are substantially more consistent with subsequent replication studies, with selection-adjusted confidence intervals providing better uncertainty quantification than uncorrected estimates.

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.

Mediation analysis of 1154 lung cancer cases and 1136 controls examined how rs1051730 in the CHRNA5-A3 locus associates with lung cancer risk. The SNP showed both direct association with lung cancer and indirect effects mediated through smoking behavior (pack-years, 7.6% of effect) and COPD (11.5% of effect), with COPD also mediating the relationship between smoking and lung cancer (32.1% of effect).

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 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 review examines genome-wide association studies (GWAS) methodology and challenges in genetic dissection of complex traits. The authors review study design, genotyping platforms, quality control, and statistical analysis approaches for GWAS, citing key examples including associations of rs1051730 (CHRNA3) with lung cancer and nicotine dependence, rs10484554 (HLA-C) with AIDS nonprogression and psoriasis, rs2476601 (PTPN22) with Crohn's disease and type 1 diabetes, and BCL11A variants with fetal hemoglobin levels.