Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE. Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs. BMC Genet 8: 10

Duke University, Durham, North Carolina, United States
BMC Genetics (Impact Factor: 2.4). 02/2007; 8(1):10. DOI: 10.1186/1471-2156-8-10
Source: DOAJ


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.
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).
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.

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Available from: Qing-Rong Liu
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    • "Significant ADHD-SLC9A9 associations in humans were reported from candidate gene studies [Brookes et al., 2006; Markunas et al., 2010] and SLC9A9 achieved one of the lowest P-values in an ADHD genomewide association study (GWAS) ($10 À5 ; [Lasky-Su et al., 2008]). In another GWAS, SLC9A9 was nominally associated with nicotine dependence [Uhl et al., 2007], which is also associated with ADHD [Monuteaux et al., 2007; Biederman et al., 2009]. "
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    • "As for most drug dependence GWAS (except perhaps nicotine dependence) monoamine system genes were conspicuous for their absence. GWAS for nicotine cessation mentioned above examined different nicotine cessation methods: denicotinized cigarettes (Drgon, Johnson et al., 2009), mecamylamine/nicotine replacement (Uhl et al., 2007) and bupropion (Uhl et al., 2008d). Using data from these studies a " quit success " genotype score was developed to assess the cumulative genetic contribution to quit success (Rose et al., 2010). "
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