ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure.
paper
Cited
Public
- Authors
- Nelson, Elliot C; Lynskey, Michael T; Heath, Andrew C; Wray, Naomi; Agrawal, Arpana; Shand, Fiona L; Henders, Anjali K; Wallace, Leanne; Todorov, Alexandre A; Schrage, Andrew J; Saccone, Nancy L; Madden, Pamela A F; Degenhardt, Louisa; Martin, Nicholas G; Montgomery, Grant W
- Year
- 2013
- Journal
- JAMA psychiatry
- PMID
- 23303482
- DOI
- 10.1001/jamapsychiatry.2013.282
- PMCID
- PMC3789525
CONTEXT: The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging. OBJECTIVE: 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. DESIGN: Case-control genetic association study that included 2 control groups (lacking an established optimal control group). SETTING: Semistructured psychiatric interviews. PARTICIPANTS: 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. MAIN OUTCOME MEASURE: Lifetime heroin dependence. RESULTS: 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). CONCLUSIONS: 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.
Figure
Linkage disequilibrium analysis of select TTC12, ANKK1, and DRD2 gene single-nucleotide polymorphisms (r2 values are shown).
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| Name | Type |
|---|---|
| African American | cohort |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| alcohol-related outcomes | phenotype |
| alcohol-related phenotypes | phenotype |
| ANKK1 | gene |
| any illicit drug local | drug |
| apomorphine | drug |
| Asian | cohort |
| astrocytes | phenotype |
| ATR controls local | cohort |
| ATR Controls local | cohort |
| Australian Twin Registry (ATR) controls local | cohort |
| brain | anatomy |
| cannabis dependence | phenotype |
| cannabis use | phenotype |
| cases | cohort |
| CATS Pilot Project Participants local | cohort |
| CEPH trio 1334 local | cohort |
| chromosome 11 gene cluster local | gene |
| cocaine | phenotype |
| COGA sample | cohort |
| Collaborative Study on the Genetics of Alcoholism (COGA) family data local | cohort |
| combined heroin/illicit drug dependent group local | cohort |
| comorbid alcohol and illicit drug dependence local | phenotype |
| Comorbidity and Trauma Study (CATS) local | cohort |
| Coriell Cell Repository local | cohort |
| DNA | drug |
| DRD2 | gene |
| drug dependence | phenotype |
| drug dependence liability local | phenotype |
| DSM-IV substance dependence diagnoses local | phenotype |
| European ancestry | cohort |
| Fagerström score local | phenotype |
| Finnish population-based birth cohort local | cohort |
| full sample | cohort |
| GoldenGate technology local | drug |
| heavy drinking | phenotype |
| heroin-dependent cases local | cohort |
| illicit drug dependence | phenotype |
| illicit drug-dependent neighborhood controls local | cohort |
| Illicit drug‑dependent neighborhood controls local | cohort |
| illicit drugs | phenotype |
| Illumina BeadStation local | drug |
| Illumina BeadStudio software local | drug |
| licit drug dependence local | phenotype |
| Licit drug dependence local | phenotype |
| NCAM1 | gene |
| Neighborhood control local | cohort |
| neighborhood controls local | cohort |
| Neighborhood controls local | cohort |
| Neighborhood Controls local | cohort |
| Neighborhood controls (no alcohol, illicit drugs) local | cohort |
| Neighborhood controls (no illicit drugs) local | cohort |
| Neighborhood controls (no nicotine, alcohol, illicit drugs) local | cohort |
| neighborhood controls not dependent on any illicit drugs local | cohort |
| neighborhood controls with lifetime history of illicit drug dependence local | cohort |
| neighborhood controls without lifetime history of illicit drug dependence local | cohort |
| New South Wales ORT clinics local | cohort |
| nicotine | drug |
| nicotine dependence | phenotype |
| Nicotine-related outcomes local | phenotype |
| nicotine-related phenotypes local | phenotype |
| non-cannabis illicit drug local | drug |
| non-dependent neighborhood controls local | cohort |
| Non‑dependent neighborhood controls local | cohort |
| Non-nicotine-dependent individuals local | phenotype |
| Non-opioid illicit drug dependence local | phenotype |
| opioid | drug |
| opioid dependence | phenotype |
| opioid receptor genes local | gene |
| Other illicit drug dependence local | phenotype |
| psychosis | phenotype |
| radial glia | anatomy |
| risk | phenotype |
| rs10502172 | variant |
| rs1800497 | variant |
| rs4492854 local | variant |
| rs4938012 local | variant |
| rs4938013 local | variant |
| rs7130431 local | variant |
| rs877138 local | variant |
| sedative dependence | phenotype |
| sedatives | drug |
| smoking | phenotype |
| smoking at age 14 years local | phenotype |
| smoking at age 31 years local | phenotype |
| SNP | cohort |
| stimulant | drug |
| stimulant dependence | phenotype |
| stimulants | drug |
| substance use | phenotype |
| suicide | phenotype |
| temperament | phenotype |
| tobacco dependence | phenotype |
| tobacco use | phenotype |
| TTC12 | gene |
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