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REVIEW ARTICLE
The association between an oxytocin receptor gene
polymorphism and cultural orientations
Siyang Luo •Shihui Han
Accepted: 5 May 2014 / Published online: 30 May 2014
ÓSpringer-Verlag Berlin Heidelberg 2014
Abstract Recent research has revealed an association between collectivistic cul-
tural values and allelic frequency of the serotonin transporter polymorphism (5-
HTTLPR). The current study investigated whether collectivistic cultural values are
also associated the allelic frequency of another gene, i.e., the oxytocin receptor gene
polymorphism (OXTR rs53576), which has been linked to social cognition and
behavior. In addition, we examined whether OXTR rs53576 can explain the rela-
tionships between pathogen prevalence, collectivistic cultural values and prevalence
of major depression disorder. We found that, across 12 nations, A allelic frequency
of OXTR rs53576 correlates with collectivistic cultural values. Moreover, A allelic
frequency of OXTR rs53576 mediates the relationship between pathogen preva-
lence and collectivistic cultural values. Finally, A allele frequency of OXTR
rs53576 is predictive of major depression disorder prevalence across nations and
such associated is mediated by collectivistic cultural values. Taken together, our
findings provide evidence for the mediating role of OXTR rs53576 in the associ-
ation between pathogen prevalence and cultural values and support the functional
role of OXTR rs53576 in human mental health.
Keywords Collectivistic cultural value Oxytocin receptor gene
polymorphism Pathogen prevalence Major depression disorder
S. Luo (&)S. Han
Department of Psychology, PKU-IDG/McGovern Institute for Brain Research,
Peking University, Beijing 100871, China
e-mail: ljc520ida@163.com
S. Han
e-mail: shan@pku.edu.cn
123
Cult. Brain (2014) 2(1):89–107
DOI 10.1007/s40167-014-0017-5
Introduction
Human mental processes vary significantly across countries with different cultural
backgrounds (Hofstede 2001). This notion has received widespread examinations by
psychologists during the past decades who have identified two primary cultural
orientations, namely, individualism and collectivism (Markus and Kitayama 1991;
Triandis 1995; Nisbett et al. 2001). Individualism dominates Western societies
where people tend to take responsible for themselves and be less group dependent in
emotion and behavior. In contrast, collectivistic culture dominates East Asian
societies where people care more for group interest than for individuals’ and
consider close people as integral parts of self, take responsible for ingroup members
and prefer group harmony and group development to competition (Markus and
Kitayama 1991; Triandis 1995; Nisbett et al. 2001). Cultural orientations of
individualism and collectivism produce profound influences on human behaviors,
cognition, emotion, motivation as well as self-regulation (Cross et al. 2011), and the
underlying brain mechanisms (Han and Northoff 2008; Han et al. 2013).
The culture-gene coevolutionary theory proposes that cultural traits, such as
individualism and collectivism, have evolved and are adaptive, during which
process they are related to some biological factors (Boyd and Richerson 1985).
Recent research has revealed geographical variability in historical and contempo-
rary pathogen prevalence and shown that geographical variability can predict
cultural variability in individualism-collectivism (Fincher et al. 2008). Nations with
greater historical and contemporary prevalence of infectious diseases or disease-
causing pathogens are more likely to endorse collectivistic cultural norms. A recent
research further revealed that the association between pathogen prevalence and
individualism-collectivism is mediated by short (S) allele distributions of the
serotonin transporter polymorphism (5-HTTLPR) (Chiao and Blizinsky 2010).
Moreover, S allele distributions of 5-HTTLPR can predict cultural variability via
local prevalence of mood disorders. That is, nations with greater pathogen
prevalence are more likely to have a greater population frequency of S allele of
5-HTTLPR, to endorse stronger collectivistic cultural norms, and to have lower
prevalence of mood disorders. These observations suggest that cultural values of
individualism and collectivism may serve as an adaptive, ‘anti-pathogen’ function,
protecting vulnerable geographical regions from increased spread of disease-causing
pathogens via the promotion of collectivistic social norms which is associated with
genetic selection of S allele carriers (Fincher et al. 2008; Chiao and Blizinsky 2010).
While the previous research suggests a relationship between 5-HTTLPR allele
frequency and cultural variability in individualism-collectivism, it remains unknown
whether collectivistic cultural values are also associated the allelic frequency of
other genes. The current work examined whether the oxytocin receptor gene
polymorphism (OXTR rs53576) is associated with collectivistic cultural values
across nations. In addition, we examined whether OXTR rs53576 can explain the
relationships between pathogen prevalence, collectivistic cultural values and
prevalence of major depression disorder. OXTR is located on chromosome 3p25,
spans 17 kb, contains four exons and three introns, and encodes a 389-aa
polypeptide with seven transmembrane domains belonging to the class I G protein-
90 S. Luo, S. Han
123
coupled receptor family (Inoue et al. 1994). Recent research found rs53576, a single
nucleotide polymorphisms with A and G variants in the third intron, can most likely
explain the differences in oxytocinergic functioning (Meyer-Lindenberg et al.
2011). It has been shown that A allele of OXTR rs53576 promotes deficits in
socioemotional domains such as empathy (Rodrigues et al. 2009), positive affect
(Lucht et al. 2009), emotional support seeking (Kim et al. 2010), self-esteem
(Saphire-Bernstein et al. 2011), maternal sensitivity (Bakermans-Kranenburg and
Van IJzendoorn 2008; Walum et al. 2012), prosocial temperament (Tost et al. 2010),
and trust behavior (Krueger et al. 2012). In addition, A compared to G allele has
been associated with higher levels of physiological and dispositional stress
reactivity and depressive symptomatology as well as increased risk for autism
(Wu et al. 2005; Rodrigues et al. 2009; Saphire-Bernstein et al. 2011). Moreover,
brain imaging research showed that A allele of OXTR rs53576 is associated with
greater gray matter volume in amygdala and decreased amygdala activity during
negative facial emotion processing (Tost et al. 2010).
Recent research samples of OXTR suggests a large variation of population
frequency of OXTR rs53576 A allele carriers across geographical regions. For
example, 85–90 % of individuals in a typical East Asian sample are A carriers,
while in a typical European sample only 45–55 % are A carriers (Wu et al. 2005;
Tost et al. 2010; Luo et al. under review). Given that the distribution of OXTR
rs53576 A allele is similar to that of 5-HTTLPR and that increased frequency of A
carriers with lower emotional sensitivity is in high collectivistic culture regions,
OXTR rs53576 may play an essential role in the relationship among pathogen
prevalence, individualism-collectivism culture norms and prevalence of mood
disorders.
To test this hypothesis, we reviewed published data on allelic frequency of
OXTR rs53576 across nations and examined the possible association between
OXTR rs53576 distribution and local individualism-collectivism. Moreover, we
explored the role of A allelic frequency of OXTR rs53576 in the relationships
among pathogen prevalence and individualism-collectivism using a mediation
analysis. In addition, given the prior evidence that both 5-HTTLPR and OXTR
rs53576 are correlated with depression (Pezawas et al. 2005; Thompson et al. 2011;
McQuaid et al. 2013) and that the association between 5-HTTLPR distribution and
global prevalence of mood disorders was mediated by individualism-collectivism
(Chiao and Blizinsky 2010), we further examined the association among A allelic
frequency of OXTR rs53576, individualism-collectivism and prevalence of major
depression disorders across nations.
Methods
Cross-national samples of the allelic frequency of OXTR rs53576
Data on the allelic frequency of OXTR rs53576 were compiled from 36 peer-
reviewed publications that included 14,938 individuals from 12 countries (Australia,
Finland, Germany, Italy, Japan, Korea, the Netherlands, People’s Republic of
Oxytocin receptor gene and cultural orientation 91
123
China, Sweden, Canada, UK and USA) (see Tables 1and 2for details of these
publications). All published samples were identified based on a Google Scholar
search conducted between October, 2012 and March, 2014 using one or more of the
following keywords: oxytocin receptor gene, OXTR rs53576, genotype and country.
All published studies that included allelic frequency information on the samples
genotyped for the OXTR rs53576 were included in the data analysis. Sample size
per country ranged from 110 (UK) to 3,186 (USA) individuals. Published studies
that do not meet the requirements were excluded based on the following two
exclusion criteria: either (1) no allelic frequency data was reported or allelic
frequency could not be accurately inferred from reported distribution of genotype
frequency (e.g., report combined frequency of homozygous and heterozygous
carriers of the A allele of the OXTR rs53576) or (2) participants came from different
countries and could not be differentiated.
Cross-national samples of the allelic frequency of 5-HTTLPR
Given the association between the allelic frequency of 5-HTTLPR and the cultural
value of individualism-collectivism (Chiao and Blizinsky 2010), the data of the
allelic frequency of 5-HTTLPR were compiled from 59 peer-reviewed publications
(56 peer-reviewed publications used in Chiao and Blizinsky (2010) and three
publications on Canadian subjects, see Table 2for details). These publications
included 27,281 individuals from 12 countries (Australia, Finland, Germany, Italy,
Japan, Korea, the Netherlands, People’s Republic of China, Sweden, Canada, UK
and USA).
Cross-national sample of cultural values
Due to the strong correlations between independent measures of individualism and
collectivism (r =0.80) (Fincher et al. 2008), the difference between collectivism
scores and individualism scores from the 12 nations (reversely calculated from
Hofstede 2001) were used in the current study. In addition, a modified Suh et al.’s
(1998) index that combines the differential collectivism-individualism scores and
the ratings from a cross-cultural study (Triandis 1994) was also used in the current
study (Table 2).
Cross-national samples of economic indices
Given that increased individualism may be a cultural consequence of economic
development and urbanization (Hofstede 2001), we included data of two economic
indices in the regression analyses, i.e., gross domestic product (GDP) and Gini
index, from the 12 countries in our regression analyses (Table 2). All GDP and Gini
index data were compiled from the Wikipedia (http://zh.wikipedia.org).
92 S. Luo, S. Han
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Table 1 The allele frequency of OXTR rs53576 in different studies
Study Country n OXTR rs53576 Alleles
AA % AG % GG % n A % G %
Bryant et al. (2013) Australia 185 25 13.51 72 38.92 88 47.57 370 122 32.97 248 67.03
Total 185 25 13.51 72 38.92 88 47.57 370 122 32.97 248 67.03
AVG 13.51 38.92 47.57 32.97 67.03
Malik et al. (2012) Canada 152 15 9.87 49 32.24 88 57.89 304 79 25.99 225 74.01
Kryski et al. (2014) Canada 270 55 20.37 170 62.96 183 67.78 816 280 34.31 536 65.69
Total 422 70 16.59 219 51.90 271 64.22 1120 359 32.05 761 67.95
AVG 15.12 47.60 62.83 30.15 69.85
Luo et al. under review China 862 373 43.27 407 47.22 82 9.51 1,724 1,153 66.88 571 33.12
Wang et al. (2013a) China 290 93 32.07 175 60.34 22 7.59 580 361 62.24 219 37.76
Wang et al. (2013b) China 270 80 29.63 171 63.33 19 7.04 540 331 61.30 209 38.70
Wu et al. (2005) China 195 80 41.03 98 50.26 17 8.72 390 258 66.15 132 33.85
Wu et al. (2012) China 101 47 46.53 45 44.55 9 8.91 202 139 68.81 63 31.19
Total 1,718 673 39.17 896 52.15 149 8.67 3,436 2,242 65.25 1,194 34.75
AVG 38.51 53.14 8.35 65.08 34.92
Jern et al. (2012) Finland 1,491 266 17.84 698 46.81 527 35.35 2,982 1,230 41.25 1,752 58.75
Johansson et al. (2012) Finland 63 11 17.46 34 53.97 18 28.57 126 56 44.44 70 55.56
Total 1,554 277 17.82 732 47.10 545 35.07 3,108 1,286 41.38 1,822 58.62
AVG 17.65 50.39 31.96 42.85 57.16
Lucht et al. (2009) Germany 289 37 12.8 114 39.45 138 47.75 578 188 32.53 390 67.47
Wermter et al. (2010) Germany 100 11 11 49 49 40 40 200 71 35.5 129 64.5
Total 389 48 12.34 163 41.90 178 45.76 778 259 33.29 519 66.71
AVG 11.90 44.23 43.88 34.02 65.99
Costa et al. (2009) Italy 192 18 9.37 94 48.96 80 41.67 384 130 33.85 254 66.15
Oxytocin receptor gene and cultural orientation 93
123
Table 1 continued
Study Country n OXTR rs53576 Alleles
AA % AG % GG % n A % G %
Total 192 18 9.37 94 48.96 80 41.67 384 130 33.85 254 66.15
AVG 9.37 48.96 41.67 33.85 66.15
Inoue et al. (2010) Japan 203 73 35.96 98 48.28 32 15.76 406 244 60.1 162 39.9
Kawamura et al. (2010) Japan 490 187 38.16 238 48.57 65 13.27 980 612 62.45 368 37.55
Liu et al. (2010) Japan – – – – – – 880 543 61.7 337 38.3
Total 693 260 37.52 336 48.48 97 14.00 2,266 1399 61.74 867 38.26
AVG 37.06 48.425 14.515 61.42 38.58
Kim et al. (2010) Korea 134 57 42.54 55 41.04 22 16.42 268 169 63.06 99 36.94
Kim et al. (2011) Korea 99 50 50.51 40 40.4 9 9.09 198 140 70.71 58 29.29
Total 233 107 45.92 95 40.77 31 13.30 466 309 66.31 157 33.69
AVG 46.53 40.72 12.76 66.89 33.12
Bakermans-Kranenburg
and Van IJzendoorn et al. (2008)
Netherlands 177 17 9.6 71 40.11 89 50.28 354 105 29.66 249 70.34
Luijk et al. (2011) Netherlands 546 52 9.52 269 49.27 225 41.21 1,092 373 34.16 719 65.84
Riem et al. (2011) Netherlands 80 10 12.5 38 47.5 32 40 160 58 36.25 102 63.75
Tops et al. (2011) Netherlands 45 4 8.89 22 48.89 19 42.22 90 30 33.33 60 66.67
Verbeke et al. (2013) Netherlands 141 17 12.06 53 37.59 71 50.35 282 87 30.85 195 69.15
Total 989 100 10.11 453 45.80 436 44.08 1,978 653 33.01 1,325 66.99
AVG 10.51 44.67 44.81 32.85 67.15
Walum et al. (2012) Sweden 2,309 – – – – – – 4,618 – 35 – 65
Total 2,309 4,618 35 65
AVG
Park et al. (2010) UK 110 8 7.27 41 37.27 61 55.45 220 57 25.91 163 74.09
94 S. Luo, S. Han
123
Table 1 continued
Study Country n OXTR rs53576 Alleles
AA % AG % GG % n A % G %
Total 110 8 7.27 41 37.27 61 55.45 220 57 25.91 163 74.09
AVG
Chang et al. (2014) USA 1,042 – ––––– 2,086 – 0.33 – 0.67
Cornelis et al. (2012) USA 1,229 179 14.56 559 45.48 491 39.95 2,458 917 37.31 1,541 62.69
Jacob et al. (2007) USA 114 9 7.89 44 38.6 61 53.51 228 62 27.19 166 72.81
Kim et al. (2010) USA 108 13 12.04 41 37.96 54 50 216 67 31.02 149 68.98
Kim et al. (2011) USA 152 33 21.71 68 44.74 51 33.55 304 134 44.08 170 55.92
Krueger et al. (2012) USA 108 9 8.33 43 39.81 56 51.85 216 61 28.24 155 71.76
Luijk et al. (2011) USA 522 62 11.88 234 44.83 226 43.3 1,044 358 34.29 686 65.71
Marsh et al. (2012) USA 35 3 8.57 14 40 18 51.43 70 20 28.57 50 71.43
Poulin et al. (2012) USA 447 32 7.16 185 41.39 230 51.45 894 249 27.85 645 72.15
Poulin et al. (2013) USA 704 59 8.38 284 40.34 361 51.28 1,408 402 28.55 1,006 71.45
Sturge-Apple et al. (2012) USA 193 11 5.70 64 33.16 118 61.14 386 86 22.28 300 77.72
Tabak et al. (2013) USA 162 17 10.49 61 37.65 84 51.85 324 95 29.32 229 70.68
Tost et al. (2010) USA 309 34 11 140 45.31 135 43.69 618 208 33.66 410 66.34
Total 5,125 461 11.29 1,737 42.54 1,885 46.17 10,252 2,659 32.56 5,507 67.44
AVG 10.64 40.77 48.58 28.67 63.72
Oxytocin receptor gene and cultural orientation 95
123
Table 2 Aggregate data on OXTR rs53576, 5-HTTLPR, cultural values, economic indices, pathogen prevalence and major depression prevalence
OXTR rs53576 5-HTTLPR Hofstede’s cultural
value
Suh’s cultural
value
Economic
indices
Pathogen prevalence Major depression
Prevalence(%)
N %A %G N %S %L Indi-Coll reverse Indi-Coll reverse GDP Gini PathogenHist PathogenCont
Australia 185 33.0 67.0 1,758 45.9 54.1 90 10 9.00 1.00 67,723 30.5 -0.2 27 27.40
Canada 422 32.1 67.9 479 47.0 53.0 80 20 8.50 1.50 52,232 23 -1.29 26 10.80
China 1,718 65.3 34.7 1,896 75.2 24.8 20 80 2.00 8.00 6,076 47 1 37 3.60
Finland 1,491 41.4 58.6 4,269 42.5 57.5 63 37 7.15 2.85 46,098 26 -0.8 25 9.45
Germany 389 33.3 66.7 4,105 43.0 57.0 67 33 7.35 2.65 41,513 28 -0.93 24 9.90
Italy 192 33.9 66.1 876 48.5 51.5 76 24 6.80 3.20 33,115 33 0.22 26 9.90
Japan 693 61.8 38.2 1,176 80.3 19.7 46 54 4.30 5.70 46,736 38.1 0.51 28 7.60
Korea 233 66.3 33.7 931 79.5 20.5 18 82 2.40 7.60 23,113 35.1 0 32 3.60
Netherlands 989 33.0 66.0 989 42.7 57.3 80 20 8.50 1.50 46,142 30.9 -0.93 24 17.90
Sweden 2,309 34.7 65.3 752 43.6 56.4 71 29 7.55 2.45 55,158 23 -0.93 25 19.50
UK 110 25.9 74.1 5,888 44.0 56.0 89 11 8.95 1.05 38,589 34 -0.96 26 18.30
USA 5,125 32.7 67.3 4,162 44.5 55.5 91 9 9.55 0.45 49,922 45 -0.86 29 21.40
96 S. Luo, S. Han
123
Cross-national samples of pathogen prevalence
Given the association between pathogen prevalence and the cultural value of
individualism-collectivism (Fincher et al. 2008), the current study used data of both
contemporary and historical pathogen prevalence for multiple regression analyses
and mediation analyses (Table 2).
Cross-national samples of lifetime prevalence of major depression disorder
Data on global lifetime prevalence of major depression disorder were compiled
from the world mental health surveys hosted by World Health Organization (Kessler
and U
¨stu
¨n2008; Chiao and Blizinsky 2010) and three peer-reviewed publications.
The mediation analyses included the 12 nations (Australia, Finland, Germany, Italy,
Japan, Korea, the Netherlands, People’s Republic of China, Sweden, Canada, UK
and USA) (Table 2).
Statistical analysis
Standard multiple regression and mediation analytic techniques were used to
explore the relationship among cultural traits of collectivism-individualism, the
allelic frequency of OXTR rs53576 and global prevalence of pathogens. First,
multiple regression analyses were conducted to examine whether cultural values of
individualism-collectivism predict gene frequency of the oxytocin receptor gene
rs53576 across 12 nations. Second, multiple regression analyses were conducted to
examine whether genetic (allelic frequencies of 5-HTTLPR and OXTR rs53576),
economic and disease factors predict cultural values of individualism-collectivism
across 12 nations. Third, mediation analyses were conducted to determine the extent
to which the allele frequency of OXTR rs53576 mediates the associations between
pathogen prevalence and cultural values of individualism-collectivism across the 12
nations. Fourth, multiple regression analyses were conducted to examine whether
the allelic frequency of OXTR rs53576 predict lifetime prevalence of major
depression disorder across the 12 nations. Finally, mediation regression analyses
were conducted to determine the extent to which cultural values of individualism-
collectivism mediate the association between OXTR rs53576 allelic frequency and
major depression disorder prevalence across the 12 nations. The Sobel test (Sobel
1982) was conducted to confirm the significance of the mediator in the mediation
analyses.
Geographical regions defined by nation served as the unit of analysis for all
primary analyses given that numerous prior studies have shown that geopolitical
regions are reliable proxies of societal cultures (Schwartz 2004; Fincher et al. 2008).
In addition, each study also served as the unit of analyses in the following
correlation analyses that explored the relationship between prevalence of the A
allele and cultural values of individualism-collectivism.
Oxytocin receptor gene and cultural orientation 97
123
Results
The associations between OXTR rs53576 and cultural values
We first assessed the global association between the allelic frequency of OXTR
rs53576 and cultural values indexed by the differential collectivism-individualism
scores. This revealed a significant correlation between A allelic frequency of OXTR
re53576 and collectivistic cultural values (r(38) =0.93, p\0.001, Fig. 1a),
suggesting that populations dominated by stronger collectivistic cultures comprise
more A carriers of OXTR rs53576. The strong correlation between the prevalence of
A allele and collectivistic cultural values was replicated when the modified Suh’s
index of collectivism cultures was used (r(38) =0.94, p\0.001, Table 3). The
analysis based on nation units also revealed that increased collectivism was
significantly positively correlated with increased prevalence of A alleles, irrespec-
tive of the difference within a nation group (r(12) =0.95 and 0.95, ps \0.001,
Fig. 1b; Table 3).
We also conducted a multiple regression analysis to determine the specificity of
the association between OXTR rs53576 and collectivistic values. The differential
collectivism-individualism score was the criterion variable. Predictor variables
include the frequency of A allele carriers and four other economic and health factors
(i.e., GDP per capita, Gini index, historical and contemporary pathogen prevalence,
Table 3 Correlations between two levels of OXTR rs53576 allele frequency and two measures of
individualism/collectivism
Criterion variable Predictor variables btpvalue
By publication (n =38) IND-COL(Hofstede) % A allele 0.93 15.20 p\0.001***
IND-COL(Suh) % A allele 0.94 16.35 p\0.001***
By nation (n =12) IND-COL(Hofstede) % A allele 0.95 9.57 p\0.001***
IND-COL(Suh) % A allele 0.95 10.01 p\0.001***
*** p\0.001
Fig. 1 Illustrations of the correlations between two levels of OXTR rs53576 allele frequency and
collectivistic cultural values
98 S. Luo, S. Han
123
Fincher et al. 2008). Results indicated that the A allelic frequency was the most
significant predictor of collectivistic values across the 12 nations (b=0.85,
p\0.001, Table 4). This result was replicated using Suh’s index of collectivistic
values (b=0.70, p\0.003, Table 4).
We further conducted a multiple regression analysis to determine whether the
frequency of A allele carriers of OXTR rs53576 can predict collectivistic cultural
values when controlling the frequency of S allele carriers of 5-HTTLPR. The
criterion variable was collectivistic cultural value. The predictor variables were the
frequency of A allele carriers of OXTR rs53576 and frequency of S allele carriers of
5-HTTLPR. It was found that only A allele frequency of OXTR rs53576 was a
significant predictor (b=1.32, p\0.005, Table 5) and this was replicated when
Suh’s index of collectivistic value was used (b=0.97, p\0.05, Table 5).
OXTR mediates associations between pathogen and cultural values
Given that S allelic frequency of 5-HTTLPR mediates the association between
historical pathogen prevalence and collectivistic cultural values (Chiao and
Table 4 Results from multiple regression analyses examining the association between cultural values of
individualism–collectivism and the oxytocin receptor gene rs53576 across nations
Criterion variable Predictor variables btpvalue
IND-COL (Hofstede) % A allele 0.85 12.66*** p\0.001***
GDP -0.34 -6.74** p=0.001**
Gini index -0.29 -4.79** p\0.01**
pathogen historical -0.13 -2.12 p=0.08
pathogen contemporary 0.15 1.68 p=0.14
IND-COL (Suh) % A allele 0.70 9.19*** p\0.001***
GDP -0.35 -5.95** p=0.001**
Gini index -0.24 -3.46* p=0.01*
pathogen historical 0.14 2.05 p=0.09
pathogen contemporary 0.05 0.51 p=0.63
*p\0.05; ** p\0.01; *** p\0.001
Table 5 Results from the mediation regression analysis examining the relationship among oxytocin
receptor gene rs53576, serotonin transporter gene and cultural values of individualism-collectivism across
nations
Criterion variable Predictor variables btpvalue
IND-COL(Hofstede) % A allele 1.32 4.16 p\0.005**
% S allele -0.39 -1.22 p=0.25
IND-COL(Suh) % A allele 0.97 2.95 p\0.02*
% S allele -0.02 -0.06 p=0.96
*p\0.05
Oxytocin receptor gene and cultural orientation 99
123
Blizinsky 2010), we also tested the specificity of the mediating role of the allelic
frequency of OXTR rs53576 in the association between contemporary and historical
pathogen prevalence and collectivistic cultural values. In the first step, we sought to
determine whether contemporary and historical pathogen prevalence was associated
with the allelic frequency of OXTR rs53576 as well as collectivistic cultural values
across nations. The prevalence of both contemporary and historical pathogen was
significantly positively correlated with the frequency of A allele carriers of OXTR
Fig. 2 a Illustration of mediation analyses among historical pathogen prevalence, A allele frequency of
OXTR rs53576 and collectivistic cultural values across the 12 nations. bIllustration of mediation
analyses among contemporary pathogen prevalence, A allele frequency of OXTR rs53576 and
collectivistic cultural values across the 12 nations
Fig. 3 Illustration of the
correlation between OXTR
rs53576 allele frequency and
lifetime prevalence of major
depressive disorder
100 S. Luo, S. Han
123
rs53576 (historical: b=0.77, p\0.005; contemporary: b=0.77, p\0.005). In
addition, across the 12 nations, the prevalence of both contemporary and historical
pathogen positively predicted the collectivistic cultural values (historical: b=0.68,
p\0.02; contemporary: b=0.73, p\0.01). In the second step, we examined
whether the frequency of A allele carriers of OXTR rs53576 was associated with
collectivistic cultures across the 12 nations. This revealed that the frequency of A
allele was a significantly positive predictor of collectivistic cultural values
(b=0.94, p\0.001, Fig. 1b), nations with a higher frequency of A allele carriers
of OXTR rs53576 showed higher collectivistic cultural values.
In the mediation regression, when both contemporary pathogen prevalence and A
allelic frequency of OXTR rs53576 were included as predictors of global
collectivistic cultural values across 12 nations, the frequency of A allele carriers
remained a reliable predictor (b=0.93, p=0.001, Fig. 2a), whereas the effect of
contemporary pathogen prevalence decreased significantly (from b=0.73 to
b=0.00; Sobel test Z =3.38, p\0.001, Fig. 2a). Similarly, when both historical
pathogen prevalence and the frequency of A allele carriers were included as
predictors in the mediation regression, the frequency of A allele carriers remained a
reliable predictor (b=1.05, p\0.001, Fig. 2b), whereas the effect of historical
pathogen prevalence decreased significantly (b=0.68 to b=-0.13; Sobel test
Z=3.53, p\0.001, Fig. 2b). These results indicate a significant mediating role of
Table 6 Results from the mediation regression analysis examining the relationship among oxytocin
receptor gene rs53576, cultural values of individualism-collectivism and major depressive disorder across
nations
Criterion variable Predictor variables btpvalue
Major depressive disorder % A allele 0.63 1.11 p=0.30
IND-COL(Hofstede) -1.42 -2.51 p\0.05*
Major depressive disorder % A allele 0.66 1.11 p=0.30
IND-COL(Suh) -1.45 -2.43 p\0.05*
*p\0.05
Fig. 4 Illustration of the mediation analyses among A allele frequency of OXTR rs53576, collectivistic
cultural values and lifetime prevalence of major depression disorder across the 12 nations
Oxytocin receptor gene and cultural orientation 101
123
A allelic frequency between contemporary and historical pathogen prevalence and
collectivistic cultural values.
Cultural values mediates associations between OXTR and mood disorders
Finally, as collectivistic cultural values mediates the association between S allele
frequency of 5-HTTLPR and global prevalence of anxiety and mood disorders
(Chiao and Blizinsky 2010), we conducted a mediation regression to test whether
the frequency of A allele carriers of OXTR rs53576 is associated with negative
affect such as lifetime prevalence of major depression disorder across cultures and
whether such associations are mediated by cultural values. We first showed that
the frequency of A allele carriers of OXTR rs53576 was significantly positively
correlated with collectivistic cultural values (b=0.94, p\0.001, Fig. 1b).
Moreover, across the 12 nations, the frequency of A allele carriers of the OXTR
rs53576 was significantly negatively correlated with lifetime prevalence of major
depression disorder (b=-0.72, p\0.01, Fig. 3). Nations with more A allele
carriers of OXTR rs53576 showed lower prevalence of major depression disorder.
We then examined whether collectivistic cultural values were associated with
major depression disorder across cultures. It was found that collectivistic cultural
values were significantly negatively correlated with lifetime prevalence of major
depression disorder (b=-0.82, p=0.001). Nations with stronger collectivistic
cultural values showed lower lifetime prevalence of major depression disorder. In
the mediation regression analysis where both A allelic frequency of OXTR
rs53576 and collectivistic cultural values were included as predictors of global
lifetime prevalence of major depression disorder across the 12 nations, the
collectivistic cultural values was a significant predictor (b=-1.42, p\0.05,
Table 6and Fig. 4) whereas the effect of A allele frequency changed significantly
(from b=-0.72 to b=0.63; Sobel test Z =-2.67, p\0.01, Table 6and
Fig. 4). The results suggest that the collectivistic cultural values significantly
mediate the relationship between A allelic frequency and lifetime prevalence of
major depression disorder.
Similarly, when Suh’s index of collectivistic cultural values were used in the
mediation analysis, frequency of A allele carriers of OXTR rs53576 was a
significant positive predictor of collectivistic cultural values (b=0.94, p\0.001)
and a negative predictor of lifetime prevalence of major depression disorder
(b=-0.72, p\0.001). The collectivistic cultural value was also a significant
negative predictor of lifetime prevalence of major depression disorder (b=
-0.82, p=0.001). In the mediation regression where both A allelic frequency
and Suh’s index were included as predictors of global lifetime prevalence of
major depression disorder across the 12 nations, collectivistic cultural value
remained a reliable predictor (b=-1.45, p\0.05), whereas the effect of A
allele frequency changed significantly (from b=-0.72 to b=0.66; Sobel test
Z=-2.61, p\0.01). These results suggest that A allelic frequency of OXTR
rs53576 predicts lifetime prevalence of major depression disorder through
collectivistic cultural values.
102 S. Luo, S. Han
123
Discussion
The current work first showed evidence for the association between collectivistic
cultural values and A allelic frequency of OXTR rs53576. There are more A allele
carriers in nations that are more strongly dominated by collectivistic cultural values.
This is similar to the association between S allelic frequency of 5-HTTLPR and
collectivistic cultural values (Chiao and Blizinsky 2010). The association between
collectivistic cultural values and A allelic frequency of OXTR rs53576 across
nations stands when using different indexes of cultural values and when
socioeconomic and health factors are controlled. This association is also evident
when S allelic frequency of 5-HTTLPR is controlled.
Similar to the previous research (Chiao and Blizinsky 2010), our analyses
showed positive correlations between contemporary (and historical) pathogen
prevalence and collectivistic cultural values. Moreover, these associations are fully
mediated by A allelic frequency of OXTR rs53576. Thus the mediating role of A
allelic frequency of OXTR rs53576 here is similar to that of S allelic frequency of
5-HTTLPR. Previous behavioral genetics studies have shown an association
between polymorphisms of 5-HTTLPR and depression (Pezawas et al. 2005).
Moreover, the frequency of 5-HTTLPR S allele carriers who are more sensitive to
negative emotion predicts decreased prevalence of mood disorder owing to
collectivistic cultures (Chiao and Blizinsky 2010). Similarly, the current work found
that the frequency of OXTR rs53576 A allele carrier with lower emotional
sensitivity can predict the global prevalence of major depression disorder, and this
association is mediated by collectivistic cultural values. It has been shown that
OXTR rs53576 predicts symptoms of depression and anxiety across individuals
(Thompson et al. 2014; McQuaid et al. 2013). The present work provides macro-
scale evidence that cultural values play an adaptive role in buffering genetically
vulnerable populations from a potentially increasing epidemiological prevalence of
mental health disorders. In addition, genetic selection of OXTR rs53576 A allele
within collectivistic cultures can explain the decreased prevalence of mood
disorders like depression. Taken together, our results highlight the importance of
genetic factors in explaining cultural differences, and how variation in cultural and
genetic factors can interact to produce mental illness across the globe.
There has been biological evidence for the association between the serotonergic
system and the oxytocinergic system. For example, both serotonin and oxytocin
modulate affiliative responses to partners and offsprings (Emiliano et al. 2007).
Both the serotonergic and oxytonergic system genes were associated with parenting
(Bakermans-Kranenburg and Van IJzendoorn 2008), empathy (Luo et al. under
review; Gyurak et al. 2013) and depressive symptoms (Pezawas et al. 2005;
Thompson et al. 2011; McQuaid et al. 2013). In addition, Lee et al. (2003) found
that serotonin stimulates hypothalamus to release oxytocin as precursor molecule.
Galfi et al. (2005) further showed that the serotonergic system directly influences
oxytocin secretion in rats. Moreover, serotonergic fibers have preferential input to
oxytonergic regions in macaques and other animals (Emiliano et al. 2007). These
findings indicate interactions between the oxytonergic and serotonergic systems in
the brain. However, to date, it remains unclear how the two genes related to the
Oxytocin receptor gene and cultural orientation 103
123
oxytonergic and serotonergic systems, OXTR and 5-HTTLPR, interact with each
during evolution. Increasing evidence suggests that A compared to G allele carriers
tend to exhibit lower emotional sensitivity such as empathy, emotional support
seeking and maternal sensitivity (Rodrigues et al. 2009; Kim et al. 2010; Saphire-
Bernstein et al. 2011; Bakermans-Kranenburg and Van IJzendoorn 2008; Walum
et al. 2012). Our findings suggest a possibility that cultural values of individualism
and collectivism are adaptive and may weaken the risks of genetic vulnerability
(i.e., S allele carriers of 5-HTTLPR) for negative emotions (e.g., anxiety) through
the selection of low emotional sensitivity genes (G allele carriers of OXTR
rs53576). This, however, should be clarified in future research.
The present study is not without limitations. For example, our existing
knowledge of cultural and genetic variation is limited as we examined data from
only 12 nations. The results of the current work should be examined in future
research when data from additional countries from Africa and the Middle East are
reported. It is important to test the role of OXTR rs53576 in the association between
5-HTTLPR, pathogen prevalence, and cultural values across more countries and
larger samples. In addition, causal inferences cannot be determined based
correlational data reported in this study. Therefore, although the results of
mediation analyses imply directionality, future studies are required to involve
genotyping, behavioral priming of individualism-collectivism, and depression
patients in order to advance out understanding of the causal links between genetic
makeup, cultural value, and pathogen prevalence.
In summary, the current findings suggest significant relationships between cultural
values of individualism-collectivism and allelic variation of OXTR rs53576, as well
as the interplay between these variables in predicting prevalence of major depression
disorder. The results reported in our study highlight the importance of culture-gene
co-evolutionary theory in studying the predictive factors behind human’s mental
states and social behaviors. Future research should examine other specific genetic
polymorphisms that may be associated with different dimensions of cultural values, as
well as environment-culture-gene interactions that influence the psychological and
neural processes underlying complex human behavior (Chiao and Blizinsky 2010;
Chudek and Henrich 2011; Kim and Sasaki 2014).
Acknowledgments This work was supported by National Basic Research Program of China (973
Program 2010CB833903), National Natural Science Foundation of China (Project 91332125,
81161120539, 91024032, 91224008), Beijing Municipal Natural Science Foundation (No.
Z111107067311058) and the Ministry of Education of China (Project 20130001110049).
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