title: Evidence of CNIH3 involvement in opioid dependence.
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.
authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.lastname: Heath
authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.lastname: Demers
authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Columbia University College of Physicians and Surgeons, New York, NY, USA.
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authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
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authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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authors.lastname: Henders
authors.affiliation: University of Connecticut School of Medicine, Farmington, CT, USA.
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authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.affiliation: Faculty of Science Medicine & Health, University of Wollongong, Wollongong, Australia.
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authors.initials: SG
authors.lastname: Schwab
authors.affiliation: Black Dog Institute, Sydney, Australia.
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authors.lastname: Shand
authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.lastname: Wallace
authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
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authors.lastname: Wang
authors.affiliation: The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.
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authors.initials: NR
authors.lastname: Wray
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA.
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authors.lastname: Zhou
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authors.lastname: Martin
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authors.initials: AR
authors.lastname: Hariri
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Yale School of Medicine, New Haven, CT, USA.
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authors.lastname: Gelernter
authors.affiliation: Department of Psychiatry, Washington University, St Louis, MO, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Bierut
authors.affiliation: Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: D J
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authors.lastname: Clark
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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mesh_terms: D000679:Amygdala / Q000000981:diagnostic imaging / Q000503:physiopathology; D000818:Animals; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006185:Habituation, Psychophysiologic / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008815:Mice, Inbred Strains; D009293:Opioid-Related Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D055815:Young Adult; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
chemical_list: D018091:Receptors, AMPA; C000613318:Cnih2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C000613316:CNIH3 protein, human; C000613317:CNIH3 protein, mouse