Evidence of CNIH3 involvement in opioid dependence.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Nelson, EC; Agrawal, A; Heath, AC; Bogdan, R; Sherva, R; Zhang, B; Al-Hasani, R; Bruchas, MR; Chou, Y-L; Demers, CH; Carey, CE; Conley, ED; Fakira, AK; Farrer, LA; Goate, A; Gordon, S; Henders, AK; Hesselbrock, V; Kapoor, M; Lynskey, MT; Madden, PAF; Moron, JA; Rice, JP; Saccone, NL; Schwab, SG; Shand, FL; Todorov, AA; Wallace, L; Wang, T; Wray, NR; Zhou, X; Degenhardt, L; Martin, NG; Hariri, AR; Kranzler, HR; Gelernter, J; Bierut, LJ; Clark, DJ; Montgomery, GW

Published Date

  • May 2016

Published In

Volume / Issue

  • 21 / 5

Start / End Page

  • 608 - 614

PubMed ID

  • 26239289

Pubmed Central ID

  • 26239289

Electronic International Standard Serial Number (EISSN)

  • 1476-5578

International Standard Serial Number (ISSN)

  • 1359-4184

Digital Object Identifier (DOI)

  • 10.1038/mp.2015.102


  • eng