Evidence of CNIH3 involvement in opioid dependence
Open accessAbstract
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.
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GWAS implicated α4 and α5 nicotinic receptor subunits in vulnerability to nicotine dependence and a SNP regulating trafficking and gating of AMPA-selective glutamate receptors (CNIH3) in opioid dependence.
“For example, genome-wide association studies have implicated two acetylcholine receptors, the α4 nicotinic receptor subunit157 and α5 nicotinic receptor subunit,158 in the vulnerability to nicotine dependence and a single-nucleotide polymorphism associated with regulating the trafficking and gating properties of AMPA-selective glutamate receptors (CNIH3) in opioid dependence.159”
From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [159]
The Results (Confirmation of association findings) report genome-wide significant associations between CNIH3 SNPs and opioid dependence, while the Discussion describes CNIH3 as an AMPA-receptor auxiliary protein that affects receptor deactivation and desensitization. The paper does not establish that an associated SNP itself regulates AMPA-receptor trafficking or gating. Citation 159 is attached to the opioid-dependence clause, not the separate nicotine-dependence claims. (LLM, conf=0.83)
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Neurobiology of addiction: a neurocircuitry analysis
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- Authors
- 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.
- Affiliations
- Washington University in St. Louis (US)
- Boston University (US)
- 23andMe (United States) (US)
- Columbia University (US)
- Icahn School of Medicine at Mount Sinai (US)
- QIMR Berghofer Medical Research Institute (AU)
- University of Connecticut (US)
- King's College London (GB)
- University of Wollongong (AU)
- Black Dog Institute (AU)
- The University of Queensland (AU)
- St. Jude Children's Research Hospital (US)
- UNSW Sydney (AU)
- Duke University (US)
- University of Pennsylvania (US)
- Yale University (US)
- Stanford Medicine (US)
- Corresponding author
- Nelson, E C
- ORCID
- Nelson, E C
- Heath, A C
- Bogdan, R
- Sherva, R
- Zhang, B
- Bruchas, M R
- Demers, C H
- Carey, C E
- Fakira, A K
- Farrer, L A
- Goate, A
- Gordon, S
- Henders, A K
- Hesselbrock, V
- Kapoor, M
- Lynskey, M T
- Madden, P A F
- Rice, J P
- Saccone, N L
- Schwab, S G
- Shand, F L
- 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
- Montgomery, G W
- Venue
- Molecular Psychiatry
- Published
- 2015-08-04
- Volume
- 21
- Issue
- 5
- Pages
- 608-614
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4740268
- OpenAlex
- W1854766247
- Cited by
- 131
- References
- 63
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- 2026: 5 · 2025: 11 · 2024: 14 · 2023: 16 · 2022: 10 · 2021: 18 · 2020: 17 · 2019: 12 · 2018: 9 · 2017: 9 · 2016: 9
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
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- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
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- Research Portal (King's College London) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000881)
- Eli Lilly and Company
- Pfizer
- Yale University
- University of Pennsylvania
- National Institutes of Health (n01hg065403-000, UL1TR000142)
- National Institute on Alcohol Abuse and Alcoholism (R01 AA 11330, R01AA017535, R01AA011330, U10AA008401)
- National Institute on Aging (R01AG045231, R01AG049789)
- National Heart, Lung, and Blood Institute (HHSN268200782096C)
- National Institute on Drug Abuse (R01-DA12690, K02DA32573, R01DA23668, T32DA007313, R01 DA 12849, R01DA023668, R01 DA18432,, R01DA033369, R25DA027995, R01DA019963, R01 DA17305, DA031579, DA033369, K99DA038725, R01DA012690, R01DA013423, R01DA018432, K02DA032573, RC2DA028909, R01DA017305, DA027995, R01DA012849, R01DA031579, R21DA036826)
- National Human Genome Research Institute (R01HG007175, U01HG004422, R01HG007354, U01HG004446, N01 HG065403, U01HG004438, HHSN268200782096C)
- National Cancer Institute (P01CA089392)
- National Institute of General Medical Sciences (T32GM007205)
- National Institute of Environmental Health Sciences (R01ES024992)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Keywords
- opioid use disorder, single nucleotide polymorphisms, genetic susceptibility, opioid misuse, heritability of addiction
- MeSH terms
- Amygdala, Animals, Female, Habituation, Psychophysiologic, Humans, Male, Membrane Proteins, Mice, Inbred Strains, Opioid-Related Disorders, Nerve Tissue Proteins, Species Specificity, Receptors, AMPA, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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