ISSN 1022�7954, Russian Journal of Genetics, 2014, Vol. 50, No. 3, pp. 298–307. © Pleiades Publishing, Inc., 2014.Original Russian Text © A.V. Kazantseva, Y.Y. Kutlumbetova, S.B. Malykh, M.M. Lobaskova, E.K. Khusnutdinova, 2014, published in Genetika, 2014, Vol. 50, No. 3, pp. 341–352.

298

1 The discovery of multiple genes of monogenic dis�orders was followed by research in the field of complexdisorders and traits, including personality traits andthe genetic factors predisposing one to them. The pos�sibility for determining the personality structure arosewith the design of psychobiological models (the psy�chobiological model proposed by S. R. Cloninger [1],in particular). Psychologists differentiate tempera�ment and character. Temperament is defined as a set ofhighly heritable traits that manifest early in develop�ment, while character traits are thought to be influ�enced by different socio�cultural factors and changeduring the lifespan [2]. One of the aspects explainingthe increased research interest in the study of thegenetic basis of personality is the hypothesis that theyare intermediate phenotypes mediating psychopathol�ogy development. Moreover, socially determinedscales (character traits) have great impact, since theymight explain the character of a given individual’sviews as to how they hinder his adaptation to social lifeor how they might help in overcoming his disorder.

1 These authors contributed equally to this work.

1

According to the published data, mammals’ behav�ior is controlled by circadian rhythms generated in thesuprachiasmatic nucleus of the hypothalamus, andarginine�vasopressin (AVP), the single neuropeptidesynthesized during circadian rhythms in vivo, ispresent in this region (for review see [3]). AVP isinvolved in hypothalamic�pituitary�adrenal axis acti�vation and the regulation of social behavior (attach�ment, exploratory activity, aggressive behavior, anxi�ety) [4]. Since its activity is controlled by AVP recep�tors (1B and 1A, in particular), studies involvingAVPR1A and AVPR1B gene polymorphisms in varia�tions of social behavior have been conducted [4–9].

The promoter region of the AVPR1A gene (12q14�15) is characterized by three microsatellite loci((GT)25, RS1, and RS3) with functional significance.According to published findings, the AVPR1A gene isassociated with dancing behavior at haplotype level[10], and the microsatellite RS3 is responsible foraltruism [7] and autism [11], while RS1 is associatedwith Novelty Seeking and Harm Avoidance variation[12] and autism [4]. Other authors point to an associ�ation between rs11174811 located in 3’�untranslatedregion (3’�UTR) of AVPR1A gene and addiction [6].

2

3

Arginine�Vasopressin Receptor Gene (AVPR1A, AVPR1B) Polymorphisms and Their Relation to Personality Traits

A. V. Kazantsevaa, 1, Y. Y. Kutlumbetovab, 1, S. B. Malykhc, M. M. Lobaskovad, and E. K. Khusnutdinovaa, b

aInstitute of Biochemistry and Genetics, Ufa Scientific Branch of Russian Academy of Sciences, 450054 Ufa, Russiae�mail: Kazantsa@mail.ru

bBashkir State University, 450074 Ufa, Russiae�mail: suleimanovaulia@mail.ru

cPsychological Institute of Russian Academy of Education, 125009 Moscow, RussiadUdmurt State University, 426034 Izhevsk, Russia

Received May 27, 2013; in final form, September 27, 2013

Abstract—The present study aimed to assess the main effects of AVPR1A (rs11174811, RS1) and AVPR1B(rs28632197, rs33911258) gene polymorphisms, as well as haplotypic, GxE and GxG effects on personalitytrait variation in 1018 healthy individuals, considering gender and ethnicity confounding. Haplotype analysisrevealed an association of AVPR1A C*S� and C*L�haplotype (rs11174811 and RS1, respectively) andincreased (PFDR = 0.016) or decreased (PFDR = 0.031) Extraversion (EPI) in Bashkirs, respectively. The asso�ciation of AVPR1B G*A�haplotype (rs28632197 and rs33911258, respectively) and decreased Self�transcen�dence (TCI�125) (PFDR = 0.040) was demonstrated in the total sample and in Udmurts. GxE analysisrevealed that the birth season modulated the involvement of the AVPR1A (rs11174811) gene marker in thevariation of Persistence (TCI�125) in the total sample (PFDR = 0.012). The modulating effect of several envi�ronmental factors (ethnicity and birth season) on the association of AVPR1A and AVPR1B gene polymor�phisms and personality traits was established.

Keywords: arginine�vasopressin receptors, personality traits, G × E and G × G effect, haplotype

DOI: 10.1134/S1022795414030041

HUMAN GENETICS

RUSSIAN JOURNAL OF GENETICS Vol. 50 No. 3 2014

ARGININE�VASOPRESSIN RECEPTOR GENE (AVPR1A, AVPR1B) 299

Animal studies support the role of the AVPR1Bgene in the regulation of social behavior. In particular,AVPR1B knockout mice demonstrated a significantdecrease in aggression [13], while functional studiesreported that the selective antagonist of the 1B recep�tor caused anxiolytic and antidepressant effects [3].The association studies support the involvement of theAVPR1B (1q32) gene in the risk of aggressive behavior[8], as well as in affective and panic disorders [14–16].However, to date there are no findings reporting therole of AVPR1B gene polymorphisms in personalitytrait variations.

Reported findings supporting an associationbetween genetic factors and personality traits remaincontradictory. One of the reasons for the controversyamong different research groups includes the lack ofinclusion of environmental factors, which modulatethe association between genes and investigated traits.The present study aimed to estimate the main effect ofAVPR1A (rs11174811, RS1) and AVPR1B (rs28632197,rs33911258) gene polymorphisms, as well as haplo�typic, GxE and GxG effects on personality trait varia�tion in healthy individuals, considering gender andethnicity as covariates.

MATERIALS AND METHODS

The study included 1018 healthy individuals fromBashkortostan Republic and Udmurt Republic (Rus�sia) (mean age of 19.53 ± 2.24 years) consisting of 409Russians, 209 Tatars, 130 Bashkirs, and 189 Udmurts(68% of women). All individuals were high school stu�dents without individual or familial history of psychi�atric diseases. All enrolled individuals were subjectedto an assessment of psychological traits and demo�graphic parameters (order and birth season, place ofresidence—urban or rural residency, and smoking sta�tus). Informed consent for involvement in thisresearch was obtained from all participants.

In order to assess personality traits, the Russianversion of the Temperament and Character Inventory(TCI�125) proposed by Cloninger, assessing four tem�perament traits (Novelty Seeking, Harm Avoidance,Reward Dependence, Persistence) and three charac�ter traits (Self�directedness, Cooperation, Self�tran�scendence), was used. TCI�125 was translated andadapted by the researchers at the Laboratory of Age�related Psychogenetics of the Psychological Instituteof RAE (Moscow).

DNA was isolated from peripheral blood lympho�cytes by standard phenol�chloroform extraction. Theconditions of amplification and restriction, as well asprimer sequences (designed using the programPrimer3: http://frodo.wi.mit.edu), are shown in Table1. Restriction was performed according to the manu�facturer’s recommendations (SibEnzyme, Russia).

To identify associations between genotypes, demo�graphic factors and personality traits, statistical analy�

sis included a one�way analysis of variance (ANOVA)in seven groups (in the total sample, men, women,Russians, Tatars, Bashkirs and Udmurts) (SPSS 13.0,PLINK v.1.07). Alleles of the microsatellite RS1 ofAVPR1A gene were combined according to Tansey etal. [4] (S—short allele and L—long allele) for the sta�tistical analysis. Linkage disequilibrium (LD) betweenpairs of AVPR1A and AVPR1B gene loci and analysis ofhaplotype association with personality traits was con�ducted using PLINK v.1.07 [17]. Haplotypes with afrequency under 1% were excluded from the analysis.Genotypes and demographic parameters (ethnicity,gender, order and birth season, residency (urban /rural), and smoking status) were the independent vari�ables in the GxE analysis, while personality traits werethe dependent variables (PLINK v.1.07). Categoricalvariables with more than two categories were trans�formed into a dummy variable matrix using PLINKv.1.07 and were used in GxE analysis. To assess theGxE effect, a series of linear regression analysis withthe regression coefficients as outputs were carried out;the sign of the regression coefficient reflects the effectof the presence of each additional minor allele(according to the manual guide for PLINK v.1.07).For instance, a positive sign of the regression coeffi�cient indicates increased mean values in personalitytraits (i.e. an increased GxE effect) in minor allele car�riers if the independent variables (environmental fac�tors) are coded as “1.” Conversely, a negative sign ofthe regression coefficient stands for a decrease in themean values of the analyzed personality traits (i.e.decreased G × E effect) in minor allele carriers if theindependent variables were coded as “1.” AVPR1A*Aof rs11174811, AVPR1A*L of RS1, AVPR1B*A ofrs28632197, AVPR1B*G of rs33911258 are the minoralleles. To evaluate the effect size and model quality, adetermination coefficient (r2) was calculated.

Since statistical analysis included multiple hypoth�esis testing, the FDR (false discovery rate) procedurewas performed to control for multiple testing [18],which makes it possible to reduce type I errors and iscongruent with the permutation test. Corrected P�val�ues (PFDR) are demonstrated in the present study. Thenumber of independent tests were: 21 for ANOVA(analysis of four polymorphisms (two of which,rs28632197 and rs33911258 in AVPR1B gene were instrong linkage disequilibrium) performed in 7 groups);28 for haplotype analysis (carried out in 7 groups); 56for GxE analysis (analysis of four polymorphisms con�ducted for 14 different dummy variables); 28 for G × Ganalysis (analysis of the four loci combinations per�formed in 7 groups).

RESULTS AND DISCUSSION

Analysis of polymorphisms in AVPR1A(rs11174811, RS1) and AVPR1B (rs28632197,rs33911258) genes was performed and their involve�ment in personality trait variation in healthy individu�

300

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KAZANTSEVA et al.

als, considering gender, ethnicity and socio�demo�graphic factors, was demonstrated. The distribution ofallele and genotype frequencies of AVPR1A andAVPR1B gene markers were consistent with the Hardy�Weinberg equilibrium: P = 0.797 for rs11174811(AVPR1A), P = 0.067 for RS1 (AVPR1A), P = 0.103 forrs28632197 (AVPR1B), P = 0.076 for rs33911258(AVPR1B). The scores of all scales of psychologicalinventories (TCI�125, EPI) were normally distributed.

Association Analysis of the Arginine�Vasopressin Receptor 1A Gene and Personality Traits

No association between AVPR1A (rs11174811,RS1) gene polymorphisms and personality traits wasrevealed in ANOVA. The following haplotype analysisdemonstrated an association of AVPR1A C*S� andC*L�haplotypes (consisting of rs11174811 and RS1,respectively) and increased (PFDR = 0.016, r2 = 0.139)or decreased Extraversion (EPI) (PFDR = 0.031; r2 =0.126) in Bashkirs (Fig. 1a). Linkage disequilibrium

(D') between the markers and haplotype frequencies inAVPR1A gene in all groups are shown in Table 2.

Animal studies support the role of the AVPR1Agene in variations in some types of social behavior inrodents: in particular, AVPR1A antagonist caused adecrease in aggression (review [3]), while decreasedAVPR1A resulted in reduced anxiety and social behav�ior deficits in voles [19]. The present study also dem�onstrated an involvement of the AVPR1A gene inExtraversion, characterizing the level of social activityin humans. The possible role of the microsatellite inthe promoter region of the AVPR1A gene in socialbehavior was reported by Hammock and Young [20].Particularly, the presence of microsatellite variantswith a high degree of homology in humans andbonobo, characterized by high levels of social interac�tion, was demonstrated; whereas 360 bp deletion wasdetected in the promoter gene region in the chimpan�zee was characterized by low levels of social attach�ment [20]. The studied RS1 microsatellite in 5'�UTRof the gene is functional; RS1 short allele (here and

Table 1. Gene polymorphisms, primers sequences, PCR conditions and allele nomenclature of analyzed markers

Gene Polymorphism Primer sequence PCR conditionsRestriction

endonuclease and allele size, bp

AVPR1A rs11174811 5'�ggttcctcacatattattggtcta�3'5'�tgctttgcaattgttagatgagtg�3'

94°C – 4 min;35 cycles:94°C – 30 s,56°C – 30 s,72°C – 30 s;72°C – 5 min

XbaI *A (400)*C (379 + 21)

RS1 5'�ctttccaggccccatggcatcc�3'5'�atagggtggtggcctctcagga�3'

94°C – 4 min;35 cycles:94°C – 30 s,58°C – 30 s,72°C – 30 s;72°C – 5 min

*8R (348)*9R (352)*10R (356)*11R (360)*12R (364)*13R (368)*15R (376)*16R (380)

AVPR1B rs28632197 5'�tgtggctttcaccatctctatg�3'5'�aagtcccttggtgactcttcag�3'

94°C – 4 min;35 cycles:94°C – 30 s,60°C – 30 s,72°C – 30 s;72°C – 5 min

BstHHI *A (279)*G (141 + 138)

rs33911258 5'�ctggttctagaccggcctct�3'5'�gtatttgcgtccccaagggat�3'

EcoRV *C (181)*T (160+ 21)

RUSSIAN JOURNAL OF GENETICS Vol. 50 No. 3 2014

ARGININE�VASOPRESSIN RECEPTOR GENE (AVPR1A, AVPR1B) 301

hereafter the nomenclature of RS1 and RS3 allelescorresponds to study [4]) results in decreased tran�scriptional activity in a human neuroblastoma cell line[4] and in increased amygdala activation in healthyindividuals [5]. Obviously, RS1 short alleles areinvolved in inhibited transcription of the AVPR1A geneand increased amygdala activity, resulting in lowersocial activity and altruism [4]. An association of theAVPR1A S�allele of RS1 (as AVPR1A C*S�haplotype)and increased Extraversion (EPI) in Bashkirs is con�tradictory to the results reported by Tansey et al. [4], aswell as to another research group reporting higherNovelty Seeking (correlating with Extraversion) andlower Harm Avoidance in healthy carriers of theAVPR1A RS1 L�allele in Caucasians [5]. This incon�sistency might be caused by the mutual influence oftwo polymorphisms (RS1, rs11174811) as haplotypeon AVPR1A gene expression rather than by RS1 itself,together with differences in sample size (about 250healthy individuals in [5]) or the presence of a psychi�atric disease (autism in [4]).

According to in silico analysis conducted inmirSNP database (http://202.38.126.151/hmdd/mirsnp/search/), rs11174811 resides in the microRNA(hsa�miR�335�3p) binding site with AVPR1A mRNAand thus probably affects mRNA stability and AVPR1Agene expression: the presence of C�allele probablycauses increased binding, which, in turn, promotesmRNA degradation. Analysis in silico is congruentwith the study of AVPR1A gene expression levels in thehuman prefrontal cortex conducted by Maher et al.[6]; the level of mRNA expression was higher inAVPR1A A�allele carriers compared to those bearingthe C/C�genotype. To date there are no publishedstudies demonstrating an association of rs11174811and personality traits. Genome�wide association stud�ies analyzing ~ 1500 loci revealed an association ofrs11174811 and spousal satisfaction and addiction inmen [6]. However, the results were contradictory, sinceopposite findings in the analysis of clinical samplesand replication studies were obtained. To date no pub�lished studies investigating the functional effect of RS1and rs11174811 interaction were published. Animalstudies demonstrated the relationship betweenthedecreased activity of AVPR1A gene and a social activitydeficit [19]. To the contrary, our results supports theneed for social contacts in individuals bearing AVPR1AC*S�haplotype, which is probably associated withdecreased AVPR1A gene expression. The possibilityexists for a compensatory effect reducing the level ofarginine�vasopressin receptor 1A by neurotransmittersystem genes (dopaminergic system, in particular [7]),resulting in higher sociability traits.

Multiple publications focused on the study of theRS3 microsatellite, also located in the 5'�UTR ofAVPR1A gene. Decreased gene promoter activityin situ in the presence of the RS3 short allele wasreported [4]. Several authors revealed an associationbetween the presence of the RS3 long allele (associ�

ated with increased AVPR1A gene expression) andlower altruism in an economic game in pre�schoolchildren [7], as well as autism [11]—a disorder char�acterized by social and communicative behavior defi�cits. We demonstrated a statistically significant increasein social activity in healthy individuals (higher Extraver�sion) in the presence of the AVPR1A RS1 S�allele, associ�ated with decreased AVPR1A gene expression. Accord�ingly, our findings are consistent with the resultsreported for RS3 in some extent [7, 11].

Association Analysis of Arginine Vasopressin Receptor 1B Gene and Personality Traits

As a result of ANOVA, an association betweenAVPR1B gene polymorphisms (rs28632197,

16

14

12

10

PFDR = 0.016 PFDR = 0.031

Haplotypesgene

AVPR1A:

A*LC*L

A*S

C*S

Extraversion, score

12

10

4

PFDR = 0.040

Haplotypesgene

AVPR1A:

A*A

A*G

G*G

G*A

Self�transcendence, score

6

8Tota

l

Men

Wom

enRuss

ians

Tatar

sBas

hkirs

Udm

urts

(a)

(b)

sam

ple

Fig. 1. Association analysis of AVPR1A (based onrs11174811, RS1) and AVPR1B gene haplotypes (based onrs28632197, rs33911258) and Extraversion (EPI) and Self�transcendence (TCI�125) in the studied groups. a � meanscores of Extraversion (EPI) (ordinate axis) in individualscarrying different AVPR1A gene haplotypes in the studiedgroups (abscissa axis). Haplotypes with low frequency areshown in gray; those with high frequency are in black.Arrows indicate associations of haplotypes and personalitytraits after correction for multiple testing.

302

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KAZANTSEVA et al.

rs33911258) and Self�transcendence (TCI�125) in thetotal sample and in Udmurts was observed. Thus,AVPR1B rs28632197 (Arg364His) A�allele carriers inUdmurts group (PFDR = 0.031, r2 = 0.088) and G�allele carriers in the total sample (PFDR = 0.031, r2 =0.008) demonstrated higher Self�transcendence(Table 3). Subsequent haplotype analysis revealed anassociation of AVPR1B*G*A�haplotype (rs28632197and rs33911258, respectively) and lower Self�tran�scendence (TCI� 125) in the total sample (PFDR =0.040, r2 = 0.009) and in Udmurts (PFDR = 0.040, r2 =0.088) (Fig. 1, b). Linkage disequilibrium (D') betweenmarkers and AVPR1В haplotype frequencies in allgroups are shown in Table 2.

Arginine�vasopressin receptor 1B is known to beinvolved in regulation of the hypothalamic�pituitary�adrenal axis, resulting in an increased level of adreno�

corticotropic hormone (ACTH). At the same time,AVPR1B knockout mice demonstrated decreasedaggression [13] and impaired social behavior [3]. Todate, AVPR1B gene polymorphisms were analyzed in agenome�wide association study of bipolar disorder[15], and a small peak on chromosome 1 associatedwith depression and anxiety was detected [21].According to the published data, AVPR1B gene poly�morphisms were associated with depression [16],panic disorder [9], and child aggression [8]. However,the studies investigating the role of these two markersin AVPR1B gene in personality traits variation have notbeen yet published. The study of panic disorderrevealed that the AVPR1B rs28632197 (Arg364His)A/A�genotype located in intracellular C�terminaldomain of AVPR1B gene was the risk factor for psy�chopathology development [9]. In the present study,an association of the AVPR1B rs28632197 A�allele and

Table 2. Linkage disequilibrium (D’) between the markers and haplotype frequencies of AVPR1A (rs11174811, RS1) andAVPR1B (rs28632197, rs33911258) genes

GroupHaplotype frequency

D 'A*L C*L A*S C*S

AVPR1A

Total sample 0.064 0.252 0.062 0.622 0.277

Men 0.060 0.251 0.080 0.609 0.169

Women 0.066 0.252 0.053 0.629 0.347

Tatars 0.051 0.257 0.086 0.605 0.093

Russians 0.077 0.252 0.052 0.619 0.399

Bashkirs 0.042 0.298a 0.033 0.628b 0.325

Udmurts 0.097 0.234 0.030 0.638 0.344

A*G G*G A*A G*A

AVPR1B

Total sample 0.098 0.075 0.011 0.817c 0.879

Men 0.082 0.075 0.005 0.838 0.933

Women 0.106 0.074 0.014 0.806 0.859

Tatars 0.100 0.080 0.009 0.811 0.898

Russians 0.093 0.087 0.016 0.805 0.822

Bashkirs 0.106 0.075 0.015 0.805 0.850

Udmurts 0.106 0.068 0.017 0.810c 0.836

Haplotypes reporting associations with personality traits are shown in bold: a PFDR = 0.031, b PFDR = 0.016, c PFDR = 0.040.

RUSSIAN JOURNAL OF GENETICS Vol. 50 No. 3 2014

ARGININE�VASOPRESSIN RECEPTOR GENE (AVPR1A, AVPR1B) 303

Tabl

e 3.

Mea

n s

core

s of

per

son

alit

y tr

aits

mea

sure

d w

ith

EP

I an

d T

CI�

125

and

one�

way

an

alys

is o

f var

ian

ce o

f gen

e po

lym

orph

ism

s in

the

stud

ied

grou

ps (

tota

l sam

�pl

e, m

en,

wom

en,

Tat

ars,

Rus

sian

s, B

ash

kirs

, U

dmur

ts)

@G

roup

Gen

otyp

eN

EX

TN

EU

NS

HA

RD

PS

SD

CO

OP

ST

AVPR1B rs28632197

Tota

l sa

mpl

eA

/A +

A/G

203

13.1

7 ±

5.2

412

.53

± 5

.99

10.5

9 ±

4.0

18.

48 ±

3.9

17.

12 ±

2.7

82.

28 ±

1.4

711

.82

± 5

.08

13.7

1 ±

4.7

17.

06 ±

3.9

9

G/G

815

12.6

± 5

.35

12.1

9 ±

5.7

610

.14

± 4

.14

8.21

± 4

.03

6.96

± 2

.98

2.32

± 1

.49

11.6

8 ±

5.3

813

.39

± 5

.17

6.46

± 3

.74

Men

A/A

+ A

/G52

13.0

6 ±

5.3

010

.11

± 5

.75

10.6

0 ±

3.9

68.

23 ±

3.8

26.

89 ±

2.5

62.

36 ±

1.4

011

.30

± 5

.22

13.0

8 ±

4.2

46.

34 ±

3.8

1

G/G

274

12.3

0 ±

5.2

210

.58

± 5

.55

9.58

± 4

.24

8.16

± 4

.33

6.66

± 2

.90

2.36

± 1

.49

11.2

9 ±

5.5

213

.10

± 5

.40

6.22

± 3

.88

Wom

enA

/A +

A/G

151

13.2

1 ±

5.2

313

.41

± 5

.86

10.5

8 ±

4.0

38.

58 ±

3.9

57.

21 ±

2.8

62.

26 ±

1.5

012

.01

± 5

.04

13.9

4 ±

4.8

67.

32 ±

4.0

3

G/G

541

12.7

6 ±

5.4

113

.06

± 5

.68

10.4

4 ±

4.0

58.

24 ±

3.8

57.

13 ±

3.0

132.

30 ±

1.4

911

.89

± 5

.29

13.5

4 ±

5.0

46.

59 ±

3.6

6

Tat

ars

A/A

+ A

/G54

12.5

7 ±

5.2

412

.18

± 6

.00

10.1

1 ±

4.2

38.

45 ±

4.3

17.

23 ±

3.3

32.

18 ±

1.2

912

.11

± 5

.38

13.8

6 ±

5.8

17.

52 ±

4.2

9

G/G

236

12.5

9 ±

4.9

812

.64

± 5

.53

10.2

3 ±

4.2

68.

83 ±

4.4

97.

23 ±

3.1

62.

45 ±

1.4

312

.18

± 5

.48

14.0

2 ±

5.4

66.

65 ±

3.6

7

Rus

sian

sA

/A +

A/G

8514

.46

± 4

.61

13.0

1 ±

5.7

510

.97

± 3

.69

8.51

± 3

.47

7.06

± 2

.40

2.39

± 1

.61

11.6

3 ±

4.8

613

.64

± 4

.05

6.94

± 4

.17

G/G

324

13.7

9 ±

4.6

412

.58

± 5

.03

11.1

5 ±

3.4

78.

32 ±

3.2

97.

20 ±

2.4

12.

38 ±

1.4

811

.85

± 4

.58

13.6

4 ±

3.9

16.

88 ±

3.7

7

Bas

hki

rsA

/A +

A/G

2812

.70

± 5

.34

12.3

0 ±

5.7

110

.48

± 3

.20

9.43

± 4

.58

8.09

± 2

.50

2.61

± 1

.30

12.5

7 ±

3.6

115

.91

± 3

.54

7.13

± 3

.11

G/G

102

12.5

1 ±

5.1

512

.29

± 5

.73

10.0

1 ±

3.8

28.

93 ±

4.0

47.

40 ±

2.9

72.

68 ±

1.4

211

.98

± 5

.52

14.4

4 ±

5.1

36.

55 ±

3.6

3

Udm

urts

A/A

+ A

/G42

12.7

3 ±

3.5

813

.95

± 5

.17

10.7

7 ±

2.7

48.

68 ±

2.8

06.

95 ±

2.0

32.

09 ±

1.5

113

.50

± 4

.64

13.8

6 ±

2.5

68.

41 ±

3.4

3a

G/G

147

13.0

3 ±

3.3

414

.04

± 4

.87

10.1

5 ±

2.8

48.

92 ±

2.9

27.

04 ±

1.8

62.

04 ±

1.4

112

.18

± 4

.28

14.0

1 ±

3.1

96.

59 ±

2.9

9

AVPR1B rs33911258

Tota

l sa

mpl

eG

/G +

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304

RUSSIAN JOURNAL OF GENETICS Vol. 50 No. 3 2014

KAZANTSEVA et al.

the G*A�haplotype (rs28632197 and rs33911258,respectively) and Self�transcendence were revealed.The findings reported by Keck et al. [9] are congruentwith our results to some extent, since individuals withpanic disorder are characterized by higher Self�tran�scendence [22]. To date no data reporting an associa�tion between rs33911258 (located in the 5'�UTR) andpersonality traits and/or risk for psychiatric disordersexist, despite its possible role in transcription regula�tion.

It should be noted that despite the absence of pub�lished data revealing an association of the AVPR1Bgene and Self�transcendence (TCI�125) and “assimi�lation” (Tellegen Absorption Scale, TAS), Bachner�Melman et al. [10] demonstrated an association of theAVPR1A gene haplotypes (consisting of RS3, RS1) andTAS scales in dancers. Accordingly, since “assimila�tion” correlates with spirituality and altered states ofconscientiousness [1], dance played a special role inthe sacred rituals in many cultures and is associatedwith altered states of consciousness.

Analysis of Gene�Environmentand Gene�Gene Interactions

The analysis of gene�environment interactionsrevealed that birth season mediated an association ofAVPR1A 11174811 and Persistence (TCI�125) in the

total sample (PFDR = 0.012). Thus, lower Persistencewas observed in individuals with AVPR1A rs11174811A�allele born in summer or spring (Fig. 2). Moreover,individuals born in summer demonstrated decreasedReward Dependence (TCI�125) (P = 0.004) in thepresence of AVPR1A rs11174811 A�allele; however,this association remained statistically non�signifi�cance after correction for multiple testing (PFDR =0.056). Correction for multiple comparisons resultedin the absence of either GxE models comprising ofAVPR1B gene polymorphisms or GxG models deter�mining statistically significant variation in personalitytraits.

According to the published findings [6] and ourresults, one might conclude that lower Persistence isassociated with increased AVPR1A gene expression.AVPR1A gene is expressed in brain regions associatedwith dopaminergic and reward system functioning(striatum, ventral pallidum, medial prefrontal cortex),hence, it is likely that changes in its expression mightalso modulate these systems [7]. Previously wereported the role of dopaminergic system gene(SLC6A3) in Persistence [23], which is congruent withthe results revealed by Avinun et al. [7] together withthe findings of the present study. To date there is noevidence of an association of AVPR1A rs11174811 andpersonality traits. However, several authors reportedthat male chimpanzee were characterized by greaterdominance and lower Conscientiousness in those withRS3 long allele [24] associated with increased pro�moter activity of AVPR1A gene [4]. Since Persistencepositively correlates with Conscientiousness (NEO�FFI)[25], our findings are consistent with Hopkins et al.[24] in some extent. Moreover, other authors point toassociation of RS3 long allele and autism [11] – a dis�order characterized by social and communicativebehavior deficit and decreased Persistence andReward Dependence [26] that is consistent with ourdata. On the contrary, the results of genome�wideassociation study reported an association of AVPR1Ars11174811 C/C�genotype and risk for the develop�ment of mild addiction characterized by lower Persis�tence [27]. Decreased Persistence was shown to becharacteristic for AVPR1A rs11174811 A�allele carri�ers born in spring or summer. An involvement of birthseason in personality traits variation is mediated byseasonal changes in the frequency of certain infectiousdiseases and in the diet (in particular, in vitamin Dlevel) during gestation possibly resulting congenitalstructural and functional brain changes, the level ofneurotransmitter systems activity (for review see [28]).Previously our group demonstrated an association ofSLC6A3 rs27072 G/G�genotype and higher Persis�tence (TCI�125) in healthy individuals, which iscaused by the increased dopamine level in synapse[23]. At the same time a decrease in dopamine metab�olism was shown to be characteristic for individualsborn from May to June due to the length of daylight inthe perinatal period [29]. Accordingly, one can suggest

4

3

2

1

0Autumn Winter Spring Summer

Persistence, scorePFDR = 0.012

AVPR1Ars11174811genotypes:

*C/*C*A/*A + *A/*C

Fig. 2. Mean scores of Persistence (TCI�125) determinedby the presence of distinct variant of the AVPR1A geners11174811 in healthy individuals depending on birth sea�son, according to the results of G × E analysis. Vertical linerepresents standard deviation for each group. Arrow indi�cates an association of AVPR1A genotype and Persistenceafter correction for multiple testing.

RUSSIAN JOURNAL OF GENETICS Vol. 50 No. 3 2014

ARGININE�VASOPRESSIN RECEPTOR GENE (AVPR1A, AVPR1B) 305

a deficit in dopaminergic neurotransmission anddecreased Persistence in those born during the springand summer months. Findings obtained in the presentstudy demonstrating an association of AVPR1Ars11174811 A�allele and lower Persistence only inthose born in spring or summer are at odds to datareported by Chotai and Adolfsson [29].

The role of ethnic differences in personality traits variation

A one�way analysis of the variance in personalitytraits was conducted in the present study in differentethnic groups, revealing distinct traits characteristicfor the studied ethnic groups. In particular, increasedExtraversion in Russians (P = 0.001) and NoveltySeeking (P = 0.002) compared to Tatars was observed;while Udmurts were characterized by higher Neuroti�cism (P = 0.030) compared to Tatars and lower Persis�tence (P = 0.044) compared to Bashkirs.

Moreover, ANOVA revealed differences in person�ality traits between ethnic groups depending on thegenotype: Russian AVPR1A rs11174811 A�allele carri�ers demonstrated increased Extraversion (P = 0.038)and Novelty Seeking (P = 0.002) compared to Tartars,while Russian AVPR1A RS1 L/L�genotype carriersreported increased Cooperation compared to Bashkirs(P = 0.005); Russian AVPR1A RS1 S�allele carriers werecharacterized by higher Extraversion compared to Bash�kirs (P = 0.024), and Tatar AVPR1A RS1 S�allele carriersshowed higher Harm Avoidance compared to Russians(P = 0.042).

Udmurts are characterized by an expressed stratifi�cation of traits demonstrating altruism, spirituality,and the necessity of self�realization depending on theAVPR1B gene haplotype. The revealed association ofthe most frequent AVPR1B G*A�haplotype (consist�ing of rs28632197, rs33911258) and decreased Self�transcendence (TCI�125) support statistically signifi�cant differences in this trait between individuals withvarious haplotypes. Interestingly, the involvement ofthe AVPR1B gene polymorphism in Self�transcen�dence variation was observed in Udmurts, since thisethnic group in general was characterized by highaltruism and sensitivity to other’s opinion, assessmentfrom other people, consideration the interests of thewhole family [30], i.e. behavior that describes highSelf�transcendence.

Interindividual differences in traits characterizingsocial activity (Extraversion) depending on theAVPR1A gene haplotype were identified in Bashkirs byour group. According to socio�psychological studies,Bashkirs are generally good�natured, friendly, andhospitable but less communicative [31]. The revealedassociation might be explained by lower Extraversionin Bashkirs bearing the AVPR1A RS1 S�allele com�pared to Russians (P = 0.024). This observation isunrelated to the differences in allele and genotype fre�

quencies distribution of AVPR1A and AVPR1B genepolymorphisms in various ethnic groups (P > 0.05).However, the level of ethnic differences in genes asso�ciated with complex traits were undifferentiated fromthe general level of gene pool, while an association ofa genetic marker with the trait (the personality traits inthe present study) may vary significantly between dif�ferent ethnic groups, as a result of the modifyingeffects of other genes and environmental factors [32]as demonstrated in our study.

The role of gender differences in personality trait variation

Despite the known gender dimorphism in theamygdala and lateral septum in the density of argininevasopressin (higher in men) [33], as well as gender dif�ferences in social behavior caused by treatment withthis neuropeptide (hostility in men and benevolence inwomen) [34], no published data reporting gender dif�ferences in behavior caused by the level of AVPR1Aand AVPR1B gene expression exist. Statistically signif�icant gender differences in the variation of the major�ity of the studied personality traits were revealed: Neu�roticism (P <0.001), Novelty Seeking (P = 0.001),Reward Dependence (P = 0.007), Self�directedness(P = 0.040), Self�transcendence (P = 0.013). Meanscores for all of the mentioned scales were higher inwomen compared to men. Women are known to dem�onstrate increased anxiety�related traits (Neuroti�cism, Harm Avoidance) compared to men [35]. Con�tradictory findings are known concerning approach�related traits (Novelty Seeking, Extraversion): both anExtraversion increase and decrease in women com�pared to men was shown. Interindividual differencesin personality between men and women could beexplained under biological (based on hormonal differ�ences) and socio�psychological theory (in particular,social roles model) [35].

However, further analysis revealed statisticallynon�significant differences in mean values of person�ality traits depending on AVPR1A and AVPR1B genepolymorphisms in both men and women separately (inhaplotype analysis) and between them (in G × E anal�ysis). The absence of a gender effect in the presentstudy might be explained by the analysis of polymor�phic loci only of two genes, although multiple genes ofdifferent systems are known to contribute to the sametrait variation [36]. Accordingly, future researchshould be performed that includes analysis of othercandidate genes to improve the model effect size.

CONCLUSION

As a result of the present study, an ethnically medi�ated association of AVPR1A and AVPR1B genes at thehaplotype level in personality traits characterizingsociability and Self�transcendence was observed.Moreover, the models of gene–environment interac�

3

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KAZANTSEVA et al.

tions demonstrating the involvement of birth season inthe modulation of the genetic effect in Persistencehave been established. Specific emphasis should bemade toward an association of AVPR1B gene markersand Self�transcendence, since the last affects the for�mation of individuality, spirituality, and self�actualiza�tion and predisposes one to psychopathology develop�ment in combination with other socially determinedscales.

Despite several advantages of the present study(sample homogeneity by age and education level; theinclusion of environmental factors into analysis; andthe correction for multiple comparisons, resulting inthe detection of the most significant results), otherenvironmental factors known to affect personalitytraits, including parenting style, socio�cultural andeconomic level, have not been analyzed. Furtherresearch in this field considering these environmentalfactors and interactions with genes from other systemsat the molecular level is required.

ACKNOWLEDGMENTS

The present study was supported by the RussianFoundation for Humanities grant No. 13�06�00583a)and the Russian Foundation for Basic ResearchNo. 11�04�97032�r_povolzhe_a).

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Translated by A. Kazantseva

SPELL: 1. lifespan, 2. suprachiasmatic, 3. neuropeptide