The AVPR1A Gene and Substance Use Disorders: Association, Replication, and Functional Evidence

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
Biological psychiatry (Impact Factor: 10.26). 04/2011; 70(6):519-27. DOI: 10.1016/j.biopsych.2011.02.023
Source: PubMed


The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms.
In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD).
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.
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.

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    • "We focused on the single nucleotide polymorphism (SNP) rs11174811 on the AVPR1a gene (located on chromosome 12q), because not only has it been associated with phenotypes related to anxiety/negative emotionality [e.g., stress reactivity, drug addiction, blood pressure , partnership satisfaction, and aggressive behavior (Maher et al., 2011; Nossent et al., 2011; Levran et al., 2014; Malik et al., 2014)], but also the functionality of this gene variant has been demonstrated by means of mRNA expression in postmortem brain tissue. Expression levels in samples homozygous for the major C-allele (genotype CC) were significantly lower than in samples with at least one minor A-allele (genotypes AA or CA; Maher et al., 2011). "
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    • "Also among men but not women, the RS3 repeat polymorphism of the AVP receptor 1a gene (AVPR1a) is associated with less partner bonding, but also fewer marital crises or threats of divorce (Walum et al., 2008). Interestingly, Maher et al. (2011) found that a particular single nucleotide polymorphism, rs11174811, of the AVPR1a gene is associated with men's (but not women's) greater relationship distress in a clinical sample recruited for severe drug use disorders, but the same SNP was associated with men's greater perceived marital warmth in a population-based sample. Thus, sample characteristics, and potentially other individual or contextual/relationship factors, may play a role in the function of AVP's influence on complex social behaviors. "
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