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ANKK1, TTC12, and NCAM1 Polymorphisms and Heroin Dependence Importance of Considering Drug Exposure

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ANKK1, TTC12, and NCAM1 Polymorphisms and Heroin Dependence Importance of Considering Drug Exposure ORIGINAL ARTICLE ANKK1, TTC12, and NCAM1 Polymorphisms and Heroin Dependence Importance of Considering Drug Exposure Elliot C. Nelson, MD; Michael T. Lynskey, PhD; Andrew C. Heath, DPhil; Naomi Wray, PhD; Arpana Agrawal, PhD; Fiona L. Shand, PhD; Anjali K. Henders, BS; Leanne Wallace, BS; Alexandre A. Todorov, PhD; Andrew J. Schrage, MS; Nancy L. Saccone, PhD; Pamela A. F. Madden, PhD; Louisa Degenhardt, PhD; Nicholas G. Martin, PhD; Grant W. Montgomery, PhD Context: The genetic contribution to liability for opi- all chromosome 11 cluster SNPs (PՆ.01); a similar com- oid dependence is well established; identification of the parison with neighborhood controls revealed greater dif- responsible genes has proved challenging. ferences (PՆ1.8ϫ10Ϫ4). Comparing cases (n=1459) with the subgroup of neighborhood controls not dependent Objective: To examine association of 1430 candidate on illicit drugs (n=340), 3 SNPs were significantly as- gene single-nucleotide polymorphisms (SNPs) with heroin sociated (correcting for multiple testing): ANKK1 SNP dependence, reporting here only the 71 SNPs in the chro- rs877138 (most strongly associated; odds ratio=1.59; 95% mosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) CI, 1.32-1.92; P=9.7ϫ10Ϫ7), ANKK1 SNP rs4938013, and that include the strongest observed associations. TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug–dependent Design: Case-control genetic association study that in- (n=191) and nondependent (n=340) neighborhood con- cluded 2 control groups (lacking an established optimal trols, suggesting that liability likely extends to non- control group). opioid illicit drug dependence. Aggregate heroin depen- dence risk associated with 2 SNPs, rs877138 and Setting: Semistructured psychiatric interviews. rs4492854 (located in NCAM1), varied more than 4-fold ϫ Ϫ9 Participants: A total of 1459 Australian cases ascer- (P=2.7 10 for the risk-associated linear trend). tained from opioid replacement therapy clinics, 531 neigh- borhood controls ascertained from economically disad- Conclusions: Our results provide further evidence of as- vantaged areas near opioid replacement therapy clinics, sociation for chromosome 11 gene cluster SNPs with sub- and 1495 unrelated Australian Twin Registry controls not stance dependence, including extension of liability to il- dependent on alcohol or illicit drugs selected from a twin licit drug dependence. Our findings highlight the necessity and family sample. of considering drug exposure history when selecting con- trol groups for genetic investigations of illicit drug de- Main Outcome Measure: Lifetime heroin depen- pendence. dence. JAMA Psychiatry. 2013;70(3):325-333. Author Aff Departmen Results: Comparison of cases with Australian Twin Reg- Published online January 2, 2013. Nelson, Lyn istry controls found minimal evidence of association for doi:10.1001/jamapsychiatry.2013.282 Agrawal, To and Mr Sch (Dr Saccon AMILY AND TWIN STUDIES HAVE netic association studies have had inad- University established that genetic fac- equate sample size4-10 to detect modest St Louis, M tors are responsible for a sub- effects, which, combined with publication University Wray) and stantial component of liabil- bias for positive findings, increases the like- 1,2 of Medical ity for opioid dependence. lihood of type I error. Underpowered at- Henders an However, identification of the genes asso- tempts at replication are also predisposed Martin and F 3 ciated with risk has proven challenging. to type II error. Finally, inconsistency in Brisbane, an Opioid dependence is a complex trait for findings across studies may result from dif- and Alcoho which many genes each likely account for ferences in important aspects of experimen- University 11,12 Sydney (Dr a modest portion of liability. Thus far, no tal design. This article examines a cen- Degenhardt consistently replicated findings have tral component of study design, control Shand is no Author Affiliations are listed at emerged from genetic association studies fo- group selection, in the context of a genetic Dog Institu the end of this article. cusing on opioid dependence. Most ge- association study of heroin dependence. New South JAMA PSYCHIATRY/ VOL 70 (NO. 3), MAR 2013 WWW.JAMAPSYCH.COM 325 ©2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 A number of issues are germane to determining the in the chromosome 11 cluster of genes (neural cell ad- most appropriate control group for a genetic associa- hesion molecule 1 [NCAM1; GenBank NM_000615.6], tion study of heroin dependence. Genetic and environ- tetratricopeptide repeat domain 12 [TTC12; GenBank mental factors contribute to liability for heroin use13,14 NM_017868.3], ankyrin repeat and kinase domain con- and, among users, for continued use and dependence.14 taining 1 [ANKK1; GenBank NM_178510.1], and dopa- Investigations in population-based twin samples have at- mine receptor D2 [DRD2; GenBank NM_000795.3]) for tempted to estimate the degree to which these influ- which a wealth of prior studies focusing on licit substance- ences are shared across the stages of this process for more related outcomes have reported similar associations. Our commonly used substances.15,16 However, owing to the findings exemplify the importance of considering his- low prevalence of opioid use, abuse, and dependence, tory of drug exposure in addition to drug dependence these samples lack adequate power to conduct similar ex- when selecting an appropriate control group. aminations.17 Genes whose influence on dependence is not shared with risk for substance use would not be ex- METHODS pected to display effects in the absence of substance ex- posure. Ascertainment of exposed, nondependent indi- viduals is complicated by the relatively low prevalence The Comorbidity and Trauma Study, a collaboration of inves- of heroin use,18-21 the lack of an identified population en- tigators at Washington University School of Medicine, Queens- riched with users who have survived the period of risk land Institute of Medical Research, and National Drug and Al- for developing dependence, the stigma associated with cohol Research Centre of the University of New South Wales, the drug,18,19 and high rates of progression from use to is a case-control genetic association study of heroin depen- dence. Details of data collection have been previously re- dependence due to heroin’s extreme addictivity. Heroin- ported.26,27 We again27 include data here from pilot study par- dependent individuals are nearly always dependent on ticipants (25 cases and 25 neighborhood controls) for whom 22,23 other drugs ; however, twin studies have produced protocols were identical and assessment comparable. widely varying estimates of the degree to which genetic and environmental risks for opioid dependence are shared PARTICIPANTS with other substances.1,2,14,24 Thus, it remains unclear whether those with a history of having used but not be- Cases recruited from ORT clinics in the greater Sydney, Aus- come dependent on other illicit drugs are an adequate tralia, region were required to be aged 18 years or older, to un- proxy for heroin-exposed controls. Similarly, the poten- derstand English, and to have participated in ORT for opioid tial for shared genetic risk with more common pheno- dependence. Participants reporting recent suicidal intent or cur- types may supersede the otherwise reasonable argu- rent psychosis were excluded. Individuals recruited from geo- ment25 that the use of an unassessed comparison group graphic areas in proximity to ORT clinics, termed neighbor- in genetic association studies of low-prevalence dis- hood controls, were excluded for recreational opioid use more than 5 times lifetime (data were included from 23 controls who eases results in only a mild reduction in power. These denied opioid use Ͼ5 times at screening but reported greater issues have left investigators conducting genetic asso- use with no dependence symptoms at interview); other inclu- ciation studies of heroin dependence without an obvi- sion and exclusion criteria were identical to those for cases. In- ous best choice for the most appropriate controls. In fact, stitutional review board approval was obtained from the Uni- they suggest that various alternative choices may be bet- versity of New South Wales, Washington University School of ter suited depending on whether a gene’s effects are spe- Medicine, Queensland Institute of Medical Research, and area cific to heroin dependence or shared with dependence health service ethics committees governing participating clin- on other drugs. ics. Participants provided written informed consent and were This article examines the association of single- reimbursed AU$50.00 for out-of-pocket expenses. nucleotide polymorphisms (SNPs) with heroin depen- Concerns that comparisons with neighborhood controls might 26,27 have inadequate power to detect effects on dependence that are dence in the Comorbidity and Trauma Study. We com- shared with both drug exposure and dependence on other sub- pare a large Australian sample of heroin-dependent cases stances (eg, 191 [36.0%] of the 531 neighborhood controls were (n=1459) receiving opioid replacement therapy (ORT) dependent on a nonopioid illicit drug; Supplemental Table 1, http: in New South Wales, Australia, with 2 control groups: //digitalcommons.wustl.edu/psychiatry) prompted a decision to (1) controls (n=531) ascertained from economically dis- genotype a second,
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