4.8 Article

Evidence of CNIH3 involvement in opioid dependence

期刊

MOLECULAR PSYCHIATRY
卷 21, 期 5, 页码 608-614

出版社

NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2015.102

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资金

  1. National Institute on Drug Abuse [R01 DA17305]
  2. National Institutes of Health [N01-HG-65403, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, 5T32GM007205-38, 8UL1TR000142-07]
  3. NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422]
  4. Gene Environment Association Studies (GENEVA) under GEI
  5. Collaborative Study on the Genetics of Alcoholism (COGA) [U10 AA008401]
  6. Collaborative Genetic Study of Nicotine Dependence (COGEND) [P01 CA089392]
  7. Family Study of Cocaine Dependence (FSCD) [R01 DA013423, R01 DA019963]
  8. Veterans Affairs Connecticut, Education and Clinical Center
  9. Veterans Affairs Philadelphia Mental Illness Research, Education and Clinical Center
  10. NIH GEI [U01HG004438]
  11. National Institute on Alcohol Abuse and Alcoholism
  12. National Institute on Drug Abuse
  13. NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' [HHSN268200782096C]
  14. Duke University
  15. National Institute on Drug Abuse grant [DA033369]
  16. NHMRC Fellowships
  17. ACS grant [RSG-14-049-01-DMC]
  18. National Institute on Drug Abuse grants [DA033369, DA031579]
  19. Klingenstein Third Generation Foundation
  20. National Institutes of Health (NIA) [R01-AG045231]
  21. NSF [DGE-1143954]
  22. [R01 DA23668]
  23. [K02 DA32573]
  24. [DA027995]
  25. [R01HG007354]
  26. [R01HG007175]
  27. [R01ES024992]
  28. [T32DA007313]

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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 nondependent 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 alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) glutamate system.

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