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Mol Psychiatry. 2016 May;21(5):608-14. doi: 10.1038/mp.2015.102. Epub 2015 Aug 4.

Evidence of CNIH3 involvement in opioid dependence.

Author information

1
Department of Psychiatry, Washington University, St Louis, MO, USA.
2
Boston University School of Medicine, Boston, MA, USA.
3
23andMe, Mountain View, CA, USA.
4
Columbia University College of Physicians and Surgeons, New York, NY, USA.
5
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
7
University of Connecticut School of Medicine, Farmington, CT, USA.
8
Institute of Psychiatry, King's College, London, UK.
9
Faculty of Science Medicine & Health, University of Wollongong, Wollongong, Australia.
10
Black Dog Institute, Sydney, Australia.
11
The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.
12
St Jude Children's Research Hospital, Memphis, TN, USA.
13
National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia.
14
Duke University, Durham, NC, USA.
15
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
16
Yale School of Medicine, New Haven, CT, USA.
17
Stanford University School of Medicine, Stanford, CA, USA.

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.

PMID:
26239289
PMCID:
PMC4740268
DOI:
10.1038/mp.2015.102
[Indexed for MEDLINE]
Free PMC Article

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