A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence.
- Authors
- Hancock, Dana B; Wang, Jen-Chyong; Gaddis, Nathan C; Levy, Joshua L; Saccone, Nancy L; Stitzel, Jerry A; Goate, Alison; Bierut, Laura J; Johnson, Eric O
- Year
- 2015
- Journal
- Human molecular genetics
- PMID
- 26220977
- DOI
- 10.1093/hmg/ddv303
- PMCID
- PMC4581607
Nicotine dependence is influenced by chromosome 15q25.1 single nucleotide polymorphisms (SNPs), including the missense SNP rs16969968 that alters function of the Ξ±5 nicotinic acetylcholine receptor (CHRNA5) and noncoding SNPs that regulate CHRNA5 mRNA expression. We tested for cis-methylation quantitative trait loci (cis-meQTLs) using SNP genotypes and DNA methylation levels measured across the IREB2-HYKK-PSMA4-CHRNA5-CHRNA3-CHRNB4 genes on chromosome 15q25.1 in the BrainCloud and Brain QTL cohorts [total N = 175 European-Americans and 65 African-Americans (AAs)]. We identified eight SNPs that were significantly associated with CHRNA5 methylation in prefrontal cortex: P ranging from 6.0 Γ 10(-10) to 5.6 Γ 10(-5). These SNP-methylation associations were also significant in frontal cortex, temporal cortex and pons: P ranging from 4.8 Γ 10(-12) to 3.4 Γ 10(-3). Of the eight cis-meQTL SNPs, only the intronic CHRNB4 SNP rs11636753 was associated with CHRNA5 methylation independently of the known SNP effects in prefrontal cortex, and it was the most significantly associated SNP with nicotine dependence across five independent cohorts (total N = 7858 European ancestry and 3238 AA participants): P = 6.7 Γ 10(-4), odds ratio (OR) [95% confidence interval (CI)] = 1.11 (1.05-1.18). The rs11636753 major allele (G) was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression and increased nicotine dependence risk. Haplotype analyses showed that rs11636753-G and the functional rs16969968-A alleles together increased risk of nicotine dependence more than each variant alone: P = 3.1 Γ 10(-12), OR (95% CI) = 1.32 (1.22-1.43). Our findings identify a novel regulatory SNP association with nicotine dependence and connect, for the first time, previously observed differences in CHRNA5 mRNA expression and nicotine dependence risk to underlying DNA methylation differences.
No figures extracted from this document.
No chunks β full text not yet ingested.
No entities extracted from this document yet.
No uploaded files.
No citations found.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Multiple trait association analysis revealed common genetic loci between lung cancer and heart failure. | Mu L et al. | β | 2026 | β |
| Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample. | Cinciripini PM et al. | β | 2024 | β |
| Integrative analysis of genetics, epigenetics and RNA expression data reveal three susceptibility loci for smoking behavior in Chinese Han population. | Li MD et al. | β | 2024 | β |
| Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci. | Carnes MU et al. | β | 2024 | β |
| An in-depth association analysis of genetic variants within nicotine-related loci: Meeting in middle of GWAS and genetic fine-mapping. | Mo C et al. | β | 2023 | β |
| Evaluating the causal effect of tobacco smoking on white matter brain aging: a two-sample Mendelian randomization analysis in UK Biobank. | Mo C et al. | β | 2023 | β |
| Child Maltreatment and Substance Use: A Behavior Genetic Analysis. | Azimi AM et al. | β | 2022 | β |
| Investigation of the genetic effect of 56 tobacco-smoking susceptibility genes on DNA methylation and RNA expression in human brain. | Yang Z et al. | β | 2022 | β |
| Alterations in nicotinic receptor alpha5 subunit gene differentially impact early and later stages of cocaine addiction: a translational study in transgenic rats and patients. | Forget B et al. | β | 2021 | β |
| Genetic architecture of four smoking behaviors using partitioned SNP heritability. | Evans LM et al. | β | 2021 | β |
| Genetic architecture of four smoking behaviors using partitioned <i>h</i><sup><i>2</i></sup><sub><i>SNP</i></sub> | Evans LM et al. | β | 2020 | β |
| Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution. | Icick R et al. | β | 2020 | β |
| Identification of 34 genes conferring genetic and pharmacological risk for the comorbidity of schizophrenia and smoking behaviors. | Ma Y et al. | β | 2020 | β |
| Considering Genetic Heterogeneity in the Association Analysis Finds Genes Associated With Nicotine Dependence. | Zhang X et al. | β | 2019 | β |
| Association and cis-mQTL analysis of variants in CHRNA3-A5, CHRNA7, CHRNB2, and CHRNB4 in relation to nicotine dependence in a Chinese Han population. | Liu Q et al. | β | 2018 | β |
| Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers. | Han H et al. | β | 2018 | β |
| Estimating and testing direct genetic effects in directed acyclic graphs using estimating equations. | Konigorski S et al. | β | 2018 | β |
| Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. | Hancock DB et al. | β | 2018 | β |
| Human Genetics of Addiction: New Insights and Future Directions. | Hancock DB et al. | β | 2018 | β |
| Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics. | Nedeljkovic I et al. | β | 2018 | β |
| MeQTL analysis of childhood obesity links epigenetics with a risk SNP rs17782313 near MC4R from meta-analysis. | Tang Y et al. | β | 2017 | β |
| Time to first cigarette and serum cholesterol levels. | Selya AS et al. | β | 2017 | β |
| Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence. | Zuo L et al. | β | 2016 | β |
| Smokescreen: a targeted genotyping array for addiction research. | Baurley JW et al. | β | 2016 | β |