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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.

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Acknowledgements

Funding support for the CATS was provided by the National Institute on Drug Abuse (R01 DA17305); GWAS genotyping services at the CIDR at The Johns Hopkins University were supported by the National Institutes of Health (contract N01-HG-65403). Funding for the Yale-Penn genetic studies of opioid, cocaine, or alcohol dependence was provided by the National Institutes of Health (RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, 5T32GM007205-38, 8UL1TR000142-07); and the Veterans Affairs Connecticut and Veterans Affairs Philadelphia Mental Illness Research, Education and Clinical Centers. Genotyping services at the CIDR at The Johns Hopkins University were supported by the National Institutes of Health (contract N01-HG-65403). Funding support for the SAGE was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423, R01 DA019963). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’ (HHSN268200782096C). The Duke Neurogenetics Study is supported by Duke University and National Institute on Drug Abuse grant DA033369. AA also receives support from R01 DA23668 and K02 DA32573. GWM and NRW are supported by NHMRC Fellowships. TW, BZ and XZ receive support from DA027995, R01HG007354, R01HG007175, R01ES024992 and ACS grant RSG-14-049-01-DMC. ARH receives support through National Institute on Drug Abuse grants DA033369 and DA031579. RB receives support from the Klingenstein Third Generation Foundation and the National Institutes of Health (NIA R01-AG045231). CHD receives support from T32DA007313. CEC receives support from NSF DGE-1143954.

Author information

Affiliations

  1. Department of Psychiatry, Washington University, St Louis, MO, USA

    • E C Nelson
    • , A Agrawal
    • , A C Heath
    • , R Bogdan
    • , B Zhang
    • , R Al-Hasani
    • , M R Bruchas
    • , Y-L Chou
    • , C H Demers
    • , C E Carey
    • , P A F Madden
    • , J P Rice
    • , N L Saccone
    • , A A Todorov
    • , T Wang
    •  & L J Bierut
  2. Boston University School of Medicine, Boston, MA, USA

    • R Sherva
    •  & L A Farrer
  3. 23andMe, Mountain View, CA, USA

    • E D Conley
  4. Columbia University College of Physicians and Surgeons, New York, NY, USA

    • A K Fakira
    •  & J A Moron
  5. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • A Goate
    •  & M Kapoor
  6. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • S Gordon
    • , A K Henders
    • , L Wallace
    • , N G Martin
    •  & G W Montgomery
  7. University of Connecticut School of Medicine, Farmington, CT, USA

    • V Hesselbrock
  8. Institute of Psychiatry, King’s College, London, UK

    • M T Lynskey
  9. Faculty of Science Medicine & Health, University of Wollongong, Wollongong, Australia

    • S G Schwab
  10. Black Dog Institute, Sydney, Australia

    • F L Shand
  11. The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia

    • N R Wray
  12. St Jude Children’s Research Hospital, Memphis, TN, USA

    • X Zhou
  13. National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia

    • L Degenhardt
  14. Duke University, Durham, NC, USA

    • A R Hariri
  15. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • H R Kranzler
  16. Yale School of Medicine, New Haven, CT, USA

    • J Gelernter
  17. Stanford University School of Medicine, Stanford, CA, USA

    • D J Clark

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Competing interests

Although unrelated to the current study, Dr Kranzler has been a consultant or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer and Roche. He is also a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which is supported by Lilly, Lundbeck, Abbott and Pfizer. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to E C Nelson.

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DOI

https://doi.org/10.1038/mp.2015.102

Supplementary Information is available at the Molecular Psychiatry website (http://www.nature.com/mp)

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