Evidence of CNIH3 involvement in opioid dependence

Nelson, E. C., Agrawal, A., Heath, A. C., Bogdan, R., Sherva, R., Zhang, B., Al-Hasani, R., Bruchas, M. R., Chou, Y.-L., Demers, C. H., Carey, C. E., Conley, E. D., Fakira, A. K., Farrer, L. A., Goate, A., Gordon, S., Henders, A. K., Hesselbrock, V., Kapoor, M., Lynskey, M. T., Madden, P. A. F., Moron, J. A., Rice, J. P., Saccone, N. L., Schwab, S. G., Shand, F. L., Todorov, A. A., Wallace, L., Wang, T., Wray, N. R., Zhou, X., Degenhardt, L., Martin, N. G., Hariri, A. R., Kranzler, H. R., Gelernter, J., Bierut, L. J., Clark, D. J. and Montgomery, G. W. (2015) Evidence of CNIH3 involvement in opioid dependence. Molecular Psychiatry, 21 5: 608-614. doi:10.1038/mp.2015.102


Author Nelson, E. C.
Agrawal, A.
Heath, A. C.
Bogdan, R.
Sherva, R.
Zhang, B.
Al-Hasani, R.
Bruchas, M. R.
Chou, Y.-L.
Demers, C. H.
Carey, C. E.
Conley, E. D.
Fakira, A. K.
Farrer, L. A.
Goate, A.
Gordon, S.
Henders, A. K.
Hesselbrock, V.
Kapoor, M.
Lynskey, M. T.
Madden, P. A. F.
Moron, J. A.
Rice, J. P.
Saccone, N. L.
Schwab, S. G.
Shand, F. L.
Todorov, A. A.
Wallace, L.
Wang, T.
Wray, N. R.
Zhou, X.
Degenhardt, L.
Martin, N. G.
Hariri, A. R.
Kranzler, H. R.
Gelernter, J.
Bierut, L. J.
Clark, D. J.
Montgomery, G. W.
Title Evidence of CNIH3 involvement in opioid dependence
Journal name Molecular Psychiatry   Check publisher's open access policy
ISSN 1359-4184
1476-5578
Publication date 2015-08-04
Year available 2015
Sub-type Article (original research)
DOI 10.1038/mp.2015.102
Open Access Status Not Open Access
Volume 21
Issue 5
Start page 608
End page 614
Total pages 7
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1312 Molecular Biology
2738 Psychiatry and Mental health
2804 Cellular and Molecular Neuroscience
Abstract Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.
Formatted abstract
Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55–0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP’s in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 5T32GM007205-38
8UL1TR000142-07
DA031579
DA033369
N01-HG-65403
R01 AA017535
R01 AA11330
R01 DA12690
R01 DA12849
R01 DA17305
R01 DA18432
RC2 DA028909
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
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Created: Tue, 27 Oct 2015, 20:27:14 EST by Susan Day on behalf of Queensland Brain Institute