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 Nurnberger, Jay A. Tischfield, Bernie Devlin, Robert E. Ferrell,
Galina P. Kirillova, Ralph E. Tarter, Kenneth S. Kendler, and Michael M. Vanyukov
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
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.
Key Words: Addiction, alcoholism, gene systems, genetic associa-
tion, social relationships, vasopressin
between these groups may be reflective of an overlap between
neurobiological systems influencing etiologic pathways through
among the various drug use disorders (DUDs), particularly those
onsistent with its complex etiology, the heritability of the
liability to substance use disorders is determined by the
additive effects of genes that are largely, if not entirely,
related to illicit drugs, supports the concept of common (nondrug-
specific) DUD liability (4,5), a latent trait encompassing all factors
influencing the probability of developing the disorder (6).
Progress in genetic methodology and the development of a
dense set of single nucleotide polymorphisms (SNPs) and linkage
tion of common genetic variation create conditions for genetic
studies of disorders of complex etiologic architecture like DUD.
in these studies. Nevertheless, although genome-wide association
scans have proven useful in identifying some regions influencing
variation in psychiatric/behavioral traits, a major drawback is that
signals expected for complex diseases are unlikely, given realistic
sample sizes, to meet strict thresholds for genome-wide signifi-
relevant candidate systems of genes (CSG) that influence behavior
related to drug use, as well as drug response. The CSG approach
gating some limitations of the candidate gene approach that usu-
ally targets only a few, sometimes functionally unrelated, loci. The
CSG approach is a viable alternative to both narrowly focused candi-
gene search. Testing candidate systems concurrently enables exami-
nation of a reduced portion of the genome. This approach increases
the prior probability of detecting true associations and places these
Data increasingly suggest that many neurobiological systems
parent-child bonding, affiliation with deviant peers, and marital
From the Department of Psychiatry (BSM, VIV, SJL, DLT, MK, TBB, XC, BPR,
JMH, DMD, FA, KSK), Virginia Institute for Psychiatric and Behavioral
Genetics, Virginia Commonwealth University, Richmond, Virginia; Cen-
ter for Education and Drug Abuse Research (RM, BD, REF, GPK, RET,
MMV), Department of Pharmaceutical Sciences, and Departments of
Psychiatry (BD, RET, MMV) and Human Genetics (REF, MMV), University
of Pittsburgh, Pittsburgh, Pennsylvania; GlaxoSmithKline Research and
Department of Psychiatry (AA), Washington University School of Medi-
ogy (HJE), Indiana University School of Medicine, and Department of
Education Building, University of Iowa School of Medicine, Iowa City,
Authors VIV and SJL contributed equally to this work.
way, HH 850, Baltimore, MD 21205; E-mail: email@example.com.
Received May 7, 2010; revised Feb 1, 2011; accepted Feb 3, 2011
BIOL PSYCHIATRY 2011;70:519–527
© 2011 Society of Biological Psychiatry
satisfaction, have been shown to influence the risk for a variety of
genetic bases for these pair-bonding behaviors have been studied
extensively in model organisms. The best known example is the
behaviors is thought to depend on the species-specific distribution
(12). These two homologous microsatellite polymorphisms, RS1 and
RS3,existin humans and have been linked to sibling conflict (13)
and autism, the central feature of which is impaired social inter-
actions, potentially through effects on amygdala function (14).
association of RS1-RS3 haplotypes with the personality trait re-
ward dependence (13), association of RS3 with altruistic behav-
ior (15), and a recent finding of an association between AVPR1A
and pair bonding in humans (16). Interestingly, mice lacking
AVPR1A display increased ethanol intake (17).
Herein, we describe an application of the CSG approach in a
genetic association study of 106 genes (Table S1 in Supplement 1)
tagged using 1536 SNPs in a discovery sample of substance abuse
cases and screened control subjects. In our discovery sample, we
find compelling evidence for the association of AVPR1A with sub-
stance use. Importantly, an SNP, rs11174811, in the associated re-
gion is predicted to disrupt a microRNA (miRNA) binding site. Al-
though the mechanisms are generally unknown, miRNAs are known
regulators of gene expression. Single nucleotide polymorphisms af-
licating the association with rs11174811. Considering that the risk for
including marital instability, we hypothesized that the AVPR1A-DUD
liability association is partially explained by an AVPR1A-associated so-
spousal satisfaction mediated the relationship between rs11174811
based US twin sample and a large alcoholism case-control sample.
Methods and Materials
description of the subject recruitment and the discovery and repli-
cation samples, as well as a limited description of the statistical
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
of substance abuse risk. Nuclear pedigrees were ascertained
through the father, who did (case; DUD?) or did not (control sub-
ject; DUD?) have a substance use disorder (abuse or dependence)
prescribed psychoactive drug). A DSM-III-R diagnosis was used be-
cause DSM-IV was introduced after this study started. Control sub-
jects had no Axis I or II psychiatric disorder. Both cases and control
subjects were required to have no history of psychosis, a Wechsler
Adult Intelligence Scale-Revised full-scale IQ in the normal range,
of ascertainment and first assessment.
study were male subjects 12 to 18 years of age, having a DSM-IV
diagnosis of substance dependence related to use of illicit drugs.
Probands were recruited from substance abuse treatment pro-
grams. The CEDAR and SADS subjects were self-identified Europe-
an-Americans from the same Greater Pittsburgh geographic area,
and the genomic inflation factor based on all genotyped SNPs,
evaluating the excess false-positive rate, was satisfactory at .98.
Virginia Twin Study of Psychiatric and Substance Use
Disorders. The Virginia Twin Study of Psychiatric and Substance
tic Twin Registry at Virginia Commonwealth University with mini-
the target age cohort. In this data set, we focus on 2231 self-identi-
tionalized as lifetime dependence on any illicit substance (9.68%).
Previous work in this sample has demonstrated a satisfactory
genomic inflation factor of .99 (20).
Collaborative Studies on the Genetics of Alcoholism. The
European-American male sample, ascertained for the presence/
absence of alcohol dependence, was used for replication of find-
studies of alcoholism and related traits (21,22). Recently, COGA
tiplex pedigree sample (23). Genome-wide genotypic data are
centers in the United States. The same seven centers also recruited
community probands through driver’s license records, random
mailings to employees and students at a university, and attendees
at medical and dental clinics. For the study, a sample of genetically
alcohol- dependent and community ascertained families. As de-
using Multidimensional Scaling. The final EA sample included 847
alcohol-dependent cases and 552 control subjects (n ? 1399
The main criterion for system/gene selection was participation
that selected for the large-scale genotyping by the National Insti-
tute on Drug Abuse Genetics Consortium (24). Genes (n ? 456)
were prioritized on a 1 to 5 scale and submitted for SNP selection.
of 106 first-priority candidate system genes in our panel for an
Illumina 1536 SNP oligonucleotide pool assay.
Discovery Sample. We performed a sex-stratified (Cochran-
Mantel-Haenszel test) initial association analysis on 1536 LD-tag-
ging SNPs in 106 candidate system genes in an EA sample that
included 359 male subjects affected with a DUD, 138 male control
subjects, 39 female subjects affected with a DUD, and 221 female
control subjects. Gene-wise significance was calculated using Fish-
dependence between the SNPs, a null distribution of Fisher’s com-
520 BIOL PSYCHIATRY 2011;70:519–527
B.S. Maher et al.
bined p values (25) was constructed by permuting case-control
status 1 million times. Significance of the actual p values was as-
sessed against the distribution of permuted p values.
We assessed mediation of association between an AVPR1A SNP
(rs11174811) and DUD risk in adult male subjects (CEDAR sample)
by a measure of spousal satisfaction from the Dyadic Relationship
Scale of the Family Assessment Measure (FAM) (26). This relation-
ship, with a latent FAM variable as a mediator, while modeling the
latter’s factor structure, was tested using Mplus (27).
Before the analyses testing that hypothesis, we examined the
factor structure of the FAM. The FAM Dyadic Relationship Scale
consists of 42 items organized theoretically into seven subscales
expression, involvement, control, values and norms). On this scale,
one member of a spousal pair rates his or her relationship with the
spouse. Examples of item text include, “This person still likes me
even when I argue with him/her” and “This person often ruins
(28), highly correlated (r ? .65–.8). Exploratory factor analysis
showed that after dropping a single item that loaded to its own
was verified by confirmatory factor analysis.
factor; a second order factor model with the 41 items indicating
seven latent factors (with items grouped according to the theoret-
ical scales of the original measure) loading to a single latent FAM
factor; and seven FAM subscale sum scores indicating a single la-
tent FAM variable. In each case, model fit was excellent, and the
between the measured variables (a, b, and c= paths in classic medi-
ation modeling ) across the models were nearly identical.
of 2231 EA male twins (9.68% substance dependent) ascertained
through the Virginia Twin Study of Psychiatric and Substance Use
Disorders. We used generalized linear models (nesting family ID
data by modeling the impact of genotype on phenotype while
accounting for degree of relationship (monozygotic/dizygotic).
The SNP was modeled as the number of A alleles of the associated
SNP using a linear model in PLINK (http://pngu.mgh.harvard.edu/
Assessment of Impact of rs11174811 on Expression ofAVPR1A
in Postmortem Brain Tissue
The risk-associated SNP rs11174811 is predicted to disrupt a
miRNA binding site. We predicted that, if this SNP is functional and
impacts expression, individuals carrying the minor, binding-site
disrupting allele would exhibit higher levels of AVPR1A expression.
If the human data prove consistent with the animal data (8,11),
those carrying the common allele would be at higher risk for sub-
stance abuse because of decreased AVPR1A expression mediated
by hsa-miR-578 and hsa-miR-526b (see Bioinformatic Evidence in
We assessed AVPR1A gene expression in RNA from the prefron-
tal cortex of the control group from the Stanley Medical Research
Institute sample. The Stanley Foundation Brain Collection sample
was genotyped for rs11174811 polymorphisms, which is located
within the seed sequence of two miRNAs (hsa-miR-578 and hsa-
miR-526b) predicted to bind to the 3= untranslated region of the
hsa-miR-578 and hsa-miR-526b on AVPR1A expression levels.
We assessed the impact of variation at rs11174811 on brain
expression levels of AVPR1A. A sample of 91 postmortem brain
samples (dorsolateral prefrontal cortex) from the Stanley Medical
merase chain reaction to test the functional significance of the
genetic findings. The association was tested by t test and linear
regression to account for important covariates (pH, postmortem
interval, sex, diagnosis).
The Discovery Study: CEDAR-SADS Sample
top 50 results for the single SNP analyses in male and female sub-
jects combined, as well as the results of allelic tests performed
separately by gender. The genotypic odds ratios and accompany-
ing p values derive from the Cochran-Mantel-Haenszel tests strati-
fied by gender. In each of the 50 SNPs, the Breslow-Day tests indi-
cate no heterogeneity. The allelic odds ratios are obtained in
an independent hypothesis test, we would set a Bonferroni experi-
ment-wide corrected p value for gene-wise tests at a threshold of
?4.7 ? 10?4after controlling for 106 genes.
As can be seen from Table 1, three SNPs in the AVPR1A receptor
gene, rs1587097 [p ? .0003, odds ratio (OR) ? 2.02 (1.37–3.00)],
.0008, OR ? 1.72 (1.25–2.36)] generate the most significant results.
In addition, these results are consistent across the genotypic and
and sex-specific tests and the degree of LD between the SNPs, are
strict Bonferroni correction threshold. The gene-wise permuted p
value was 3 ? 10?5. Whereas male and female subgroup tests
yielded similar odds ratios, the relatively small female sample
lacked power to yield a significant result at that effect size.
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 human indicator for
pair bonding, measured by the Dyadic Relationship Scale of the
model tested. As can be seen in Figure 2, there are significant
relationships between AVPR1A and FAM (p ? .006), FAM and DUD
(p ? .001), and between AVPR1A and DUD risk (p ? .006) in male
subjects. The latter relationship is also mediated by FAM, as indi-
cated by the significant indirect path (p ? .013). This mediation is
not complete, suggesting the involvement of additional factors in
ity. The alternative model, assuming DUD as mediator of the asso-
ciation between AVPR1A and FAM, demonstrated an equivalent fit.
Family Assessment Measure score was associated with DUD in
male subjects [p ? .0001; OR (95% confidence interval) ? 2.51
(1.80–3.50)] but not female subjects [p ? .09; OR (95% confidence
B.S. Maher et al.
BIOL PSYCHIATRY 2011;70:519–527 521
Table 1. Results of Top 50 SNPs Ranked by Combined (Cochran-Mantel-Haenszel) p Value
MAFGenotypic ORp Allelic ORp
ORp Male Allelic ORp
522 BIOL PSYCHIATRY 2011;70:519–527
B.S. Maher et al.
interval) ? 1.37 (.96–1.95)]. In a linear regression model, with the
genotype indexed in an additive fashion, the AVPR1A SNPs found
we decided to focus replication efforts in male EA samples.
Replication Studies of Association BetweenAVPR1A and
Substance Use Disorder
Replication in the VATSPSUD. The DUD liability-associated
SNP rs11174811 was genotyped and the association with depen-
dence on any illicit drug was tested. A male-specific significant
relationship (p ? .007) between dependence on any illicit sub-
stance and rs11174811 was detected. The frequency of the A allele
was 14.9% in unaffected male subjects and 12.5% in affected male
subjects. This association is thus in the direction opposite to that
was 15% and 22% in respective samples (Table 1). There was also a
modest (p ? .036) male-specific relationship between rs11174811
and perceived marital warmth.
Replication in the Collaborative Studies on the Genetics of
Alcoholism Case-Control Sample. While alcohol dependence
was not associated with rs11174811 (p ? .13), modest association
This relationship was in the same direction as in the discovery
AVPR1A Expression Studies
The expression levels in samples from 26 individuals heterozy-
gous and homozygous for the minor (T) allele of rs11174811 were
higher than in 76 individuals homozygous for the major allele (un-
paired t test with Welch’s correction, two-tailed p ? .01; Figure 3).
After controlling for relevant covariates, the significance of the
association increased (Table S2 in Supplement 1, p ? .0003).
Consistent with the hypothesis that vasopressin (AVP) may influ-
affiliative behaviors, this association is mediated in the discovery
sample, in part, by a measure of spousal relationship quality. While
association or even immediate involvement of sociobehavioral
suggests a specific genetic foundation for this relationship and
opens avenues for future research. It should be noted that the
mediation relationship suggested by our findings does not neces-
sarily identify the actual mediator of the association. The AVPR1A
gene may have pleiotropic effects on affiliative and social behav-
general socialization characteristic (e.g., attachment, peer selec-
tion, and bonding). Particularly germane, affiliation with deviant
peers is among the social behaviors with consistent evidence of a
ing significantly reduces the risk for a substance abuse outcome
(31,32,37-41). Social support or social network formation has also
been related to substance abuse patterns (42-45).
processes may explain the phenotypic overlap, specific biological
mechanisms have not been elucidated. However, many intriguing
lines of evidence exist. For example, it is possible that “narcotic
addiction operates partially through mechanisms which ensured
mammalian social bonding over the course of evolution” (46), as
supported, for instance, by involvement of the opioid system in
Table 1. (continued)
Male Allelic OR
CHR, chromosome; MAF, minor allele frequency; OR, odds ratio; SNP, single nucleotide polymorphism.
B.S. Maher et al.
BIOL PSYCHIATRY 2011;70:519–527 523
a common behavioral attribute in deviant social groups, may be
part of the repertoire of affiliative and reproductive behavior con-
sistent with Zahavi’s handicap principle (47), where potentially so-
ality characteristics convey a fitness benefit in a deviant group and
provide group protection. Drug abuse is also associated with inse-
tal to (delinquent) peer affiliation influence.
The primary neuropeptides linked to social behaviors are AVP
one of the most important relationships for human mental health
(50). Centrally released OXT facilitates social motivations and ap-
proach behavior, including maternal nurturing behaviors (51). Va-
OXT neural systems are also involved in other social behaviors,
including anxiety (54), processing of social cues (55), and social
AVP has been shown to differentially influence social communica-
tion, decreasing it in male subjects and increasing it in female
subjects (57). Vasopressin is more influential in male subjects and
OXT is more influential in female subjects (58). It is important to
consider our finding in the context of the existing literature. The
increasing AVPR1A expression would decrease marital stability in
male subjects (16). It is thus not surprising that the effect sizes for
and do not reach significance in female subjects. It is important to
thus lower statistical power.
The finding that the association of the rs11174811 with DUD
liability had opposite directions in the studies based on clinical
samples (CEDAR/SADS and COGA) and in the population-based
VATSPSUD study requires explanation. Although largely specula-
tive at this stage, several possibilities can be contemplated. The
association may be a spurious finding. This possibility conflicts,
supported by the association in another clinical sample, by the
mediational effects on the family functioning indicator consistent
This “flip-flop” (59) finding may also be possible in the case of true
allelic heterogeneity between the studies (60). Elucidation of the
source of this heterogeneity might be impossible even with dense
tion of the association may also be related to the differences in the
sample ascertainment. In both CEDAR/SADS and COGA samples,
the affected individuals, ascertained clinically, have a relatively se-
vere DUD, frequently related to polysubstance abuse, whereas in
It is conceivable that recreational drug use that does not involve/
reach clinical strength drug abuse/dependence may be itself an
attribute of affiliative behavior and thus related to the prosocial
with elevated antisociality, a frequent attribute of and precursor to
a clinical DUD that requires stepping over a higher liability thresh-
rs11174820rs11836346rs2738250 rs11174811 rs10784339rs1587097
LD Map Type: r−square
Physical Distance: 23.9 kb
0 0.2 0.4 0.6 0.81
Figure 1. Association results across the AVPR1A region for the genotypic (Cochran-Mantel-Haenszel), allelic, and sex-limited allelic tests. –Log (p) for each
the single nucleotide polymorphisms across the AVPR1A region. LD, linkage disequilibrium.
524 BIOL PSYCHIATRY 2011;70:519–527
B.S. Maher et al.
however, the flip-flop suggests caution in assigning risk or protec-
tion modalities to allelic effects in variation in complex traits.
thus cannot be rejected statistically. Nevertheless, we focused this
on the role of variation in the AVPR1A gene in social behavior and
The findings of this study, if confirmed, call for expansion of
research into the role of the AVP-OXT system variation in other
is also potentially influenced by other genetic (as well epigenetic
and nongenetic) mechanisms, some of which have already been
gene and its interaction with parenting style to liability to DUD
(61,62). It should be noted that even a nominally highly significant
methods. Establishing mediation of a detected genetic association
diate level (e.g., gene expression; premorbid trait) would provide
anistic model test.
This study was supported by the National Institute on Drug Abuse
(Grant P50DA005605 to RET; Grants R01DA011922, R01DA019157,
and K02DA018701 to MMV). The Collaborative Study on the Genetics
of Alcoholism (COGA) is supported by National Institutes of Health
Grant U10AA08401. GlaxoSmithKline partially funded genotyping
The Collaborative Study on the Genetics of Alcoholism, Principal
Investigators B. Porjesz, V. Hesselbrock, H. Edenburg, and L. Bierut,
includes 10 different centers: University of Connecticut (V. Hessel-
University of Iowa (S. Kuperman, J. Kramer); State University of New
York Downstate (B. Porjesz); Washington University in St. Louis (L.
Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San
dation (L. Almasy), Howard University (R. Taylor); and Virginia Com-
monwealth University (D. Dick). Other COGA collaborators contribut-
ing to the genome-wide association studies data set include: L. Bauer
(University of Connecticut); D. Koller, S. O’Connor, L. Wetherill, X. Xuei
gaswamy (State University of New York Downstate); A. Hinrichs, J.
Rohrbaugh, J-C Wang (Washington University in St. Louis); A. Brooks
Alcoholism Staff Collaborators. We continue to be inspired by our
memories of Henri Begleiter and Theodore Reich, founding Principal
Investigator and Co-Principal Investigator of COGA, and also owe a
Li, currently a consultant with COGA, P. Michael Conneally, Raymond
Crowe, and Wendy Reich, for their critical contributions. This national
date system genes for this study, including Andrew Bergen, Joseph
Cubells, Ken Krauter, Mary Jeanne Kreek, Sharon Murphy, Huijin Ring,
152229362916233037323951219263361320 27 34417
21283583 10 172431384 1118251 42
Total effect: -.160 (.048)***
I dit 022 ( 009)* Indirect: -.022 (.009)*
Direct: -.138 (.050)**
Chi-square: 2819.50, 852 df
CFI/TLI 843/ 833 CFI/TLI: .843/.833
(.046)( -.131 **)
Figure 2. Path model of mediation of the relationship be-
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, communi-
cation; CON, control; FAM, Family Assessment Measure; RM-
SEA, root mean square error of approximation; RP, role per-
formance; TA, task accomplishment; VN, values and norms.
gous and homozygous for the minor (T) allele of rs11174811 were higher
Welch’s correction, two-tailed p ? .01). *p ? .05.
B.S. Maher et al.
BIOL PSYCHIATRY 2011;70:519–527 525
Ming Tsuang, Kirk Wilhelmsen, Pamela A.F. Madden, Naomi Breslau,
Eric O. Johnson, Dorothy Hatsukami, Ovide Pomerleau, Gary E. Swan,
Alison M. Goate, Joni Rutter, Sarah Bertelsen, Louis Fox, Douglas Fug-
affiliated with the Department of Mental Health, Johns Hopkins
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