title: The AVPR1A gene and substance use disorders: association, replication, and functional evidence.
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.
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA. bmaher@jhsph.edu
authors.forename: Brion S
authors.initials: BS
authors.lastname: Maher
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Vladimirov
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Latendresse
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Thiselton
authors.forename: Rebecca
authors.initials: R
authors.lastname: McNamee
authors.forename: Moonsu
authors.initials: M
authors.lastname: Kang
authors.forename: Tim B
authors.initials: TB
authors.lastname: Bigdeli
authors.forename: Xiangning
authors.initials: X
authors.lastname: Chen
authors.forename: Brien P
authors.initials: BP
authors.lastname: Riley
authors.forename: John M
authors.initials: JM
authors.lastname: Hettema
authors.forename: Howard
authors.initials: H
authors.lastname: Chilcoat
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Muglia
authors.forename: E Lenn
authors.initials: EL
authors.lastname: Murrelle
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.forename: Fazil
authors.initials: F
authors.lastname: Aliev
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: John
authors.initials: J
authors.lastname: Kramer
authors.forename: John
authors.initials: J
authors.lastname: Nurnberger
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Galina P
authors.initials: GP
authors.lastname: Kirillova
authors.forename: Ralph E
authors.initials: RE
authors.lastname: Tarter
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.forename: Michael M
authors.initials: MM
authors.lastname: Vanyukov
mesh_terms: D000293:Adolescent; D000328:Adult; D001127:Arginine Vasopressin / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D005260:Female; D056726:Genetic Association Studies / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D009769:Object Attachment; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017483:Receptors, Vasopressin / Q000096:biosynthesis / Q000235:genetics*; D012727:Sex Characteristics; D018454:Spouses / Q000523:psychology*; D019966:Substance-Related Disorders / Q000235:genetics* / Q000523:psychology; D014427:Twins / Q000235:genetics / Q000523:psychology
chemical_list: D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin