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

JAMA Psychiatry (Impact Factor: 12.01). 01/2013; 70(3):1-9. DOI: 10.1001/jamapsychiatry.2013.282
Source: PubMed


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.

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    • "Participants in a case-control examination of genetic and environmental factors contributing to liability for opioid dependence (CATS) included 1468 cases (577 female, 39.3%) recruited from opioid replacement therapy (ORT) clinics in the greater Sydney, Australia region and 513 controls (284 female. 55.4%) from the geographic areas in proximity to ORT clinics who denied having used opioids recreationally more than ten times (Conroy et al. 2009; Shand et al. 2011; Nelson et al. 2013). Written informed consent was obtained from all participants as per the institutional review board (IRB) approvals obtained from the University of New South Wales, WUSM, the QIMR, and the ethics committees governing the participating clinics. "
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    ABSTRACT: Childhood maltreatment (CM) has consistently been linked with adverse outcomes including substance use disorders and adult sexual revictimization. Adult sexual victimization itself has been linked with psychopathology but has predominately been studied in women. The current investigation examines the impact of CM and co-occurring psychopathology on adult sexual victimization in men and women, replicating findings in three distinct samples. Method We investigated the association between continuous CM factor scores and adult sexual victimization in the Childhood Trauma Study (CTS) sample ( N = 2564). We also examined the unique relationship between childhood sexual abuse (CSA) and adult sexual victimization while adjusting for co-occurring substance dependence and psychopathology. We replicated these analyses in two additional samples: the Comorbidity and Trauma Study (CATS; N = 1981) and the Australian Twin-Family Study of Alcohol Use Disorders (OZ-ALC; N = 1537). Results Analyses revealed a significant association with CM factor scores and adult sexual victimization for both men and women across all three samples. The CSA factor score was strongly associated with adult sexual victimization after adjusting for substance dependence and psychopathology; higher odds ratios were observed in men (than women) consistently across the three samples. Conclusions A continuous measure of CSA is independently associated with adult sexual trauma risk across samples in models that included commonly associated substance dependence and psychopathology as covariates. The strength of the association between this CSA measure and adult sexual victimization is higher in magnitude for men than women, pointing to the need for further investigation of sexual victimization in male community samples.
    Psychological Medicine 10/2015; DOI:10.1017/S0033291715002056 · 5.94 Impact Factor
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    • "We did not find a significant association with controls who had not been screened for a history of mental illness or drinking behavior. These data highlight the importance of using the appropriate control group and to know the level of drinking in a control population, as well as family histories of psychiatric diagnoses, for true genetic associations to be assessed [Nelson et al., 2013]. It is also possible that the differences we observe between ADS cases and controls are due to population stratification. "
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene (TACR1) are nominally associated with bipolar affective disorder (BPAD) in a genome-wide association study and in several case-control samples of BPAD, alcohol dependence syndrome (ADS) and attention-deficit hyperactivity disorder (ADHD). Eighteen TACR1 SNPs were associated with BPAD in a sample (506 subjects) from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD (UCL1 and UCL2 combined: P = 2.0 × 10−3), ADS (P = 2.0 × 10−3) and BPALC (P = 6.0 × 10−4) compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1-susceptibility haplotypes identified 19 SNPs in the promoter region, 5′ UTR, exons, intron/exon junctions and 3′ UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10-fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2014; 165(4). DOI:10.1002/ajmg.b.32241 · 3.42 Impact Factor
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