The AVPR1A gene and substance use disorders: association, replication, and functional evidence.
paper
Primary
Public
- Authors
- Maher, Brion S; Vladimirov, Vladimir I; Latendresse, Shawn J; Thiselton, Dawn L; McNamee, Rebecca; Kang, Moonsu; Bigdeli, Tim B; Chen, Xiangning; Riley, Brien P; Hettema, John M; Chilcoat, Howard; Heidbreder, Christian; Muglia, Pierandrea; Murrelle, E Lenn; Dick, Danielle M; Aliev, Fazil; Agrawal, Arpana; Edenberg, Howard J; Kramer, John; Nurnberger, John; Tischfield, Jay A; Devlin, Bernie; Ferrell, Robert E; Kirillova, Galina P; Tarter, Ralph E; Kendler, Kenneth S; Vanyukov, Michael M
- Year
- 2011
- Journal
- Biological psychiatry
- PMID
- 21514569
- DOI
- 10.1016/j.biopsych.2011.02.023
- PMCID
- PMC4083653
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.
Association results across the AVPR1A region for the genotypic (Cochran-Mantel-Haenszel), allelic, and sex-limited allelic tests. −Log (p) for each single nucleotide polymorphism and association test plotted across the AVPR1A gene. The bottom panel displays linkage disequilibrium measures between the single nucleotide polymorphisms across the AVPR1A region. LD, linkage disequilibrium.
Path model of mediation of the relationship between rs11174811 and drug use disorder by spousal satisfaction measured by the Dyadic Relationship Scale of the Family Assessment Measure in male subjects. The complete factor structure of the Family Assessment Measure and its seven subscales is maintained. Significance of standardized path coefficients and effects is indicated by * < .05, ** < .01, and *** < .001. AE, affective expression; AI, involvement; CFI/TLI, Comparative Fit Index/Tucker-Lewis Index; COM, communication; CON, control; FAM, Family Assessment Measure; RM-SEA, root mean square error of approximation; RP, role performance; TA, task accomplishment; VN, values and norms.
AVPR1A expression levels in samples from 26 individuals heterozygous and homozygous for the minor (T) allele of rs11174811 were higher than in 76 individuals homozygous for the major allele (unpaired t test with Welch's correction, two-tailed p = .01). *p < .05.
| # | Section | Preview |
|---|---|---|
| 0 | Methods and Materials | Because of space constraints, the sample recruitment and methods are described in detail in… |
| 1 | Methods and Materials — Subject Recruitment — Initial Discovery Sample: Center for Education and Drug Abuse Research and Substance Abuse and the Dopamine System | The Center for Education and Drug Abuse Research (CEDAR) sample was ascertained as part of a large… |
| 2 | Methods and Materials — Subject Recruitment — Initial Discovery Sample: Center for Education and Drug Abuse Research and Substance Abuse and the Dopamine System | Probands in the Substance Abuse and Dopamine System (SADS) study were male subjects 12 to 18 years… |
| 3 | Methods and Materials — Subject Recruitment — Virginia Twin Study of Psychiatric and Substance Use Disorders | The Virginia Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD) was ascertained… |
| 4 | Methods and Materials — Subject Recruitment — Collaborative Studies on the Genetics of Alcoholism | The Collaborative Studies on the Genetics of Alcoholism (COGA) study's European-American male… |
| 5 | Methods and Materials — Subject Recruitment — Collaborative Studies on the Genetics of Alcoholism | The main criterion for system/gene selection was participation in response to more than one drug… |
| 6 | Methods and Materials — Statistical Methods — Discovery Sample | We performed a sex-stratified (Cochran-Mantel-Haenszel test) initial association analysis on 1536… |
| 7 | Methods and Materials — Mediation/Moderation Modeling | We assessed mediation of association between an AVPR1A SNP (rs11174811) and DUD risk in adult male… |
| 8 | Methods and Materials — Mediation/Moderation Modeling | Before the analyses testing that hypothesis, we examined the factor structure of the FAM. The FAM… |
| 9 | Methods and Materials — Mediation/Moderation Modeling | We applied several approaches to modeling the factor structure of the FAM: all 41 items were… |
| 10 | Methods and Materials — VATSPSUD Replication | We attempted replication of the association finding in a sample of 2231 EA male twins (9.68%… |
| 11 | Methods and Materials — COGA Replication | We tested association between rs11174811 and two core COGA phenotypic measures, alcohol dependence… |
| 12 | Methods and Materials — Assessment of Impact of rs11174811 on Expression of AVPR1A in Postmortem Brain Tissue | The risk-associated SNP rs11174811 is predicted to disrupt a miRNA binding site. We predicted that,… |
| 13 | Methods and Materials — Assessment of Impact of rs11174811 on Expression of AVPR1A in Postmortem Brain Tissue | We assessed AVPR1A gene expression in RNA from the prefrontal cortex of the control group from the… |
| 14 | Methods and Materials — Assessment of Impact of rs11174811 on Expression of AVPR1A in Postmortem Brain Tissue | We assessed the impact of variation at rs11174811 on brain expression levels of AVPR1A. A sample of… |
| 15 | Results — The Discovery Study: CEDAR-SADS Sample — Candidate System Association Analysis | Table 1 presents the top 50 results for the single SNP analyses in male and female subjects… |
| 16 | Results — The Discovery Study: CEDAR-SADS Sample — Candidate System Association Analysis | As can be seen from Table 1, three SNPs in the AVPR1A receptor gene, rs1587097 [p = .0003, odds… |
| 17 | Results — The Discovery Study: CEDAR-SADS Sample — Candidate System Association Analysis — Spousal Relationship as a Mediator of the Association of AVPR1A with DUD | To test the mediational hypothesis, we used available data on the quality of spousal relationship, a… |
| 18 | Results — The Discovery Study: CEDAR-SADS Sample — Candidate System Association Analysis — Spousal Relationship as a Mediator of the Association of AVPR1A with DUD | Family Assessment Measure score was associated with DUD in male subjects [p < .0001; OR (95%… |
| 19 | Results — Replication Studies of Association Between AVPR1A and Substance Use Disorder — Replication in the VATSPSUD | The DUD liability-associated SNP rs11174811 was genotyped and the association with dependence on any… |
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| Name | Type |
|---|---|
| addiction | phenotype |
| Addictive processes local | phenotype |
| affective expression local | phenotype |
| Affiliative and Social Behaviors local | phenotype |
| Affiliative behavior | phenotype |
| aggression | phenotype |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Alcohol-dependent probands local | phenotype |
| antisocial personality disorder | phenotype |
| anxiety | phenotype |
| AVP | drug |
| AVP-OXT system variation local | variant |
| AVPR1A | gene |
| AVPR1A SNP local | variant |
| axis I disorder | phenotype |
| Axis II Psychiatric Disorder local | phenotype |
| case-control sample | cohort |
| CEDAR local | cohort |
| CEDAR/SADS local | cohort |
| CEDAR sample local | cohort |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| communication | phenotype |
| Community probands local | cohort |
| control | cohort |
| control group (Stanley Medical Research Institute sample) local | cohort |
| dependence on any illicit drug local | phenotype |
| deviant peers | phenotype |
| Deviant social groups local | cohort |
| discovery sample | cohort |
| dorsolateral prefrontal cortex | anatomy |
| drug dependence | phenotype |
| DUD | phenotype |
| DUD+ local | phenotype |
| DUD- local | phenotype |
| DUD liability local | phenotype |
| EA male sample local | cohort |
| European-American male sample local | cohort |
| European American male twins local | cohort |
| European ancestry | cohort |
| European population | cohort |
| FAM local | phenotype |
| FAM Dyadic Relationship Scale local | phenotype |
| Family Assessment Measure score local | phenotype |
| FAM subscale sum scores local | phenotype |
| Female controls local | cohort |
| Female DUD cases local | cohort |
| female subjects | cohort |
| gene expression | phenotype |
| hsa-miR-526b local | drug |
| hsa-miR-578 local | drug |
| illicit drugs | phenotype |
| illicit drug use | phenotype |
| insecure attachment | phenotype |
| involvement | phenotype |
| latent FAM factor local | phenotype |
| LD-tagging SNPs local | variant |
| Male controls local | cohort |
| Male DUD cases local | cohort |
| male European-American sample local | cohort |
| male subjects | cohort |
| MAOA | gene |
| marital stability local | phenotype |
| maternal nurturing behaviors local | phenotype |
| maximum drinks | phenotype |
| maximum drinks in a 24-hour period local | phenotype |
| Mid-Atlantic Twin Registry local | cohort |
| Multiplex pedigree sample local | cohort |
| National Institute on Drug Abuse Genetics Consortium local | cohort |
| Opioid system | drug |
| OXT | gene |
| pair bonding | phenotype |
| Parent-Child Bonding local | phenotype |
| paternal care | phenotype |
| perceived marital warmth local | phenotype |
| polysubstance abuse | phenotype |
| prefrontal cortex | anatomy |
| processing of social cues local | phenotype |
| Prosocial Function local | phenotype |
| psychosis | phenotype |
| Recreational drug use | phenotype |
| replication sample | cohort |
| role performance local | phenotype |
| rs10784339 local | variant |
| rs11174811 local | variant |
| rs1587097 local | variant |
| SADS study local | cohort |
| scent marking local | phenotype |
| Separation distress local | phenotype |
| seven latent factors local | phenotype |
| social behavior | phenotype |
| social bonding | phenotype |
| social communication local | phenotype |
| social motivations local | phenotype |
| social recognition | phenotype |
| social support | phenotype |
| Spousal Relationship Quality local | phenotype |
| spousal satisfaction local | phenotype |
| Stanley Foundation Brain Collection sample local | cohort |
| Stanley Medical Research Institute local | cohort |
| substance abuse | phenotype |
| Substance Abuse Outcome local | phenotype |
| substance use | phenotype |
| task accomplishment local | phenotype |
| values and norms local | phenotype |
| vasopressin | drug |
| VATSPSUD | cohort |
| Virginia sample local | cohort |
| Virginia Twin Study of Psychiatric and Substance Use Disorders local | cohort |
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Discovery and evaluation of a novel <sup>18</sup>F-labeled vasopressin 1a receptor PET ligand with peripheral binding specificity. | Hu J et al. | — | 2024 | → |
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| Genomic Signatures of Positive Selection in Human Populations of the <i>OXT</i>, <i>OXTR</i>, <i>AVP</i>, <i>AVPR1A</i> and <i>AVR1B</i> Gene Variants Related to the Regulation of Psychoemotional Response. | Bakoev SY et al. | — | 2023 | → |
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