Evidence of CNIH3 involvement in opioid dependence

[Diffusé le 29-11-2015]

Source : Molecular Psychiatry 2016; 21(5): 608-14

E C. Nelson1, A. Agrawal1, A C. Heath1, R. Bogdan1, R. Sherva2, B. Zhang1, R. Al-Hasani1, M R. Bruchas1, Y-L. Chou1, C H. Demers1, C E. Carey1, E D. Conley3, A K. Fakira4, L A. Farrer2, A. Goate5, S. Gordon6, A K. Henders6, V. Hesselbrock7, M. Kapoor5, M T. Lynskey8, P A F. Madden1, J A. Moron4, J P. Rice1, N L. Saccone1, S G. Schwab9, F L. Shand10, A A. Todorov1, L. Wallace6, T. Wang1, N R. Wray11, X. Zhou12, L. Degenhardt13, N G. Martin6, A R. Hariri14, H R. Kranzler15, J. Gelernter16, L J. Bierut1, D J. Clark17, G W. Montgomery6, Professor EC Nelson

1Department of Psychiatry, Washington University, St Louis, MO, USA
2Boston University School of Medicine, Boston, MA, USA
323andMe, Mountain View, CA, USA
4Columbia University College of Physicians and Surgeons, New York, NY, USA
5Icahn School of Medicine at Mount Sinai, New York, NY, USA
6QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
7University of Connecticut School of Medicine, Farmington, CT, USA
8Institute of Psychiatry, King’s College, London, UK
9Faculty of Science Medicine & Health, University of Wollongong, Wollongong, Australia
10Black Dog Institute, Sydney, Australia
11The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia
12St Jude Children’s Research Hospital, Memphis, TN, USA
13National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia
14Duke University, Durham, NC, USA
15University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
16Yale School of Medicine, New Haven, CT, USA
17Stanford University School of Medicine, Stanford, CA, USA

Department of Psychiatry, Washington University School of Medicine, 4560 Clayton Avenue, St Louis, MO 63110, USA. E-mail: nelsone@wustl.edu

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.


Podcast Series - Sous Emprise
Noter cet article :

Ma bibliographie

Accédez à vos articles favoris, classez-les par dossiers ou encore exportez-les sous format ENDNOTE !


Rechercher

Besoin d'aide ?
Recherche avancée
Recherche par revues
798 articles actuellement disponibles
A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | 0-9
Recherche par rubriques