Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs.
paper
Cited
Public
- Authors
- Uhl, George R; Liu, Qing-Rong; Drgon, Tomas; Johnson, Catherine; Walther, Donna; Rose, Jed E
- Year
- 2007
- Journal
- BMC genetics
- PMID
- 17407593
- DOI
- 10.1186/1471-2156-8-10
- PMCID
- PMC1853105
BACKGROUND: Classical genetic studies indicate that nicotine dependence is a substantially heritable complex disorder. Genetic vulnerabilities to nicotine dependence largely overlap with genetic vulnerabilities to dependence on other addictive substances. Successful abstinence from nicotine displays substantial heritable components as well. Some of the heritability for the ability to quit smoking appears to overlap with the genetics of nicotine dependence and some does not. We now report genome wide association studies of nicotine dependent individuals who were successful in abstaining from cigarette smoking, nicotine dependent individuals who were not successful in abstaining and ethnically-matched control subjects free from substantial lifetime use of any addictive substance. RESULTS: These data, and their comparison with data that we have previously obtained from comparisons of four other substance dependent vs control samples support two main ideas: 1) Single nucleotide polymorphisms (SNPs) whose allele frequencies distinguish nicotine-dependent from control individuals identify a set of genes that overlaps significantly with the set of genes that contain markers whose allelic frequencies distinguish the four other substance dependent vs control groups (p < 0.018). 2) SNPs whose allelic frequencies distinguish successful vs unsuccessful abstainers cluster in small genomic regions in ways that are highly unlikely to be due to chance (Monte Carlo p < 0.00001). CONCLUSION: These clustered SNPs nominate candidate genes for successful abstinence from smoking that are implicated in interesting functions: cell adhesion, enzymes, transcriptional regulators, neurotransmitters and receptors and regulation of DNA, RNA and proteins. As these observations are replicated, they will provide an increasingly-strong basis for understanding mechanisms of successful abstinence, for identifying individuals more or less likely to succeed in smoking cessation efforts and for tailoring therapies so that genotypes can help match smokers with the treatments that are most likely to benefit them.
Diagram outlining the analyses undertaken in this report. (left) Comparisons between allele frequency assessments at 520,000 genomic SNPs in the whole group of European American nicotine dependent subjects who volunteered for inclusion in nicotine cessation trials in comparison to SNP frequency assessments for European-American control research volunteers without histories of any substantial use of any addictive substance. The preplanned analysis of this data focused on the extent to which these nominally positive SNPs added to the significance of the results of previously assembled convergent data from studies of other four other addict vs control comparisons. Genes for which the Monte Carlo significance increases (eg lower p values) after adding the current data to previously-obtained data are listed in Table 1. (right) Comparisons between allele frequency assessments at 520,000 genomic SNPs in two subgroups of the European American nicotine dependent research participants who volunteered for inclusion in nicotine cessation trials, described previously. NDQ subjects successfully abstained from smoking for at least 6 weeks after completion of therapeutic trials using nicotine and/or mecamylamine, NDNQ subjects did not abstain for this period. The preplanned analysis of this data focused on the extent to which the nominally-positive SNPs from this comparison clustered together in genomic regions that encoded genes in comparison to chance levels, assuming independence of SNP allelic frequencies. Genes that contain at least three nominally positive SNPs and are thus nominees to contain variants that participate in the genetic underpinnings of individual differences in smoking quit success are listed in [see additional file 1].
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