The AVPR1A gene and substance use disorders: Association, replication, and functional evidence

Brion S. Maher, Vladimir I. Vladimirov, Shawn J. Latendresse, Dawn L. Thiselton, Rebecca McNamee, Moonsu Kang, Tim B. Bigdeli, Xiangning Chen, Brien P. Riley, John M. Hettema, Howard Chilcoat, Christian Heidbreder, Pierandrea Muglia, E. Lenn Murrelle, Danielle M. Dick, Fazil Aliev, Arpana Agrawal, Howard J. Edenberg, John Kramer, John NurnbergerJay A. Tischfield, Bernie Devlin, Robert E. Ferrell, Galina P. Kirillova, Ralph E. Tarter, Kenneth S. Kendler, Michael M. Vanyukov

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background: The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms. Methods: In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD). Results: Associations (p ≤.0008) were detected with three SNPs in the arginine vasopressin 1A receptor gene, AVPR1A, with a gene-wise p value of 3 × 10 -5. Bioinformatic evidence points to a role for rs11174811 (microRNA binding site disruption) in AVPR1A function. Based on literature implicating AVPR1A in social bonding, we tested spousal satisfaction as a mediator of the association of rs11174811 with the DUD. Spousal satisfaction was significantly associated with DUD in males (p <.0001). The functional AVPR1A SNP, rs11174811, was associated with spousal satisfaction in males (p =.007). Spousal satisfaction was a significant mediator of the relationship between rs11174811 and DUD. We also present replication of the association in males between rs11174811 and substance use in one clinically ascertained (n = 1399) and one epidemiologic sample (n = 2231). The direction of the association is consistent across the clinically-ascertained samples but reversed in the epidemiologic sample. Lastly, we found a significant impact of rs11174811 genotype on AVPR1A expression in a postmortem brain sample. Conclusions: The findings of this study call for expansion of research into the role of the arginine vasopressin and other neuropeptide system variation in DUD liability.

Original languageEnglish (US)
Pages (from-to)519-527
Number of pages9
JournalBiological psychiatry
Volume70
Issue number6
DOIs
StatePublished - Sep 15 2011

Keywords

  • Addiction
  • alcoholism
  • gene systems
  • genetic association
  • social relationships
  • vasopressin

ASJC Scopus subject areas

  • Biological Psychiatry

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