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ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure.

ABSTRACT: The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging.To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations.Case-control genetic association study that included 2 control groups (lacking an established optimal control group).Semistructured psychiatric interviews.A total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample.Lifetime heroin dependence.Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (P ? .01); a similar comparison with neighborhood controls revealed greater differences (P ? 1.8 × 10(-4)). Comparing cases (n = 1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n = 340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio = 1.59; 95% CI, 1.32-1.92; P = 9.7 × 10(-7)), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n = 191) and nondependent (n = 340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P = 2.7 × 10(-9) for the risk-associated linear trend).Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.

SUBMITTER: Nelson EC

PROVIDER: S-EPMC3789525 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure.

Nelson Elliot C EC Lynskey Michael T MT Heath Andrew C AC Wray Naomi N Agrawal Arpana A Shand Fiona L FL Henders Anjali K AK Wallace Leanne L Todorov Alexandre A AA Schrage Andrew J AJ Saccone Nancy L NL Madden Pamela A F PA Degenhardt Louisa L Martin Nicholas G NG Montgomery Grant W GW

JAMA psychiatry 20130301 3

<h4>Context</h4>The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging.<h4>Objective</h4>To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations.<h4>Design</h4>Case-control genetic association study that included 2 ...[more]

PMID: 23303482

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Project description:The attention of drug-dependent persons tends to be captured by stimuli associated with drug consumption. This involuntary cognitive process is considered as attentional bias (AB). AB has been hypothesized to have causal effects on drug abuse and drug relapse, but its underlying neural mechanisms are still unclear. This study investigated the neural basis of AB in abstinent heroin addicts (AHAs), combining event-related potential (ERP) analysis and source localization techniques. Electroencephalography data were collected in 21 abstinent heroin addicts and 24 age- and gender-matched healthy controls (HCs) during a dot-probe task. In the task, a pair of drug-related image and neutral image was presented randomly in left and right side of the cross fixation, followed by a dot probe replacing one of the images. Behaviorally, AHAs had shorter reaction times (RTs) for the congruent condition compared to the incongruent condition, whereas this was not the case in the HCs. This finding demonstrated the presence of AB towards drug cues in AHAs. Furthermore, the image-evoked ERPs in AHAs had significant shorter P1 latency compared to HCs, as well as larger N1, N2, and P2 amplitude, suggesting that drug-related stimuli might capture attention early and overall require more attentional resources in AHAs. The target-related P3 had significantly shorter latency and lower amplitude in the congruent than incongruent condition in AHAs compared to HCs. Moreover, source localization of ERP components revealed increased activity for AHAs as compared to HCs in the dorsal posterior cingulate cortex (dPCC), superior parietal lobule and inferior frontal gyrus (IFG) for image-elicited responses, and decreased activity in the occipital and the medial parietal lobes for target-elicited responses. Overall, the results of our study confirmed that AHAs may exhibit AB in drug-related contexts, and suggested that the bias might be related to an abnormal neural activity, both in early and late attention processing stages.

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ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure.

Publications

ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure.

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