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Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
Converging Evidence Implicates the Dopamine D3
Receptor Gene in Vulnerability to Schizophrenia
Fuquan Zhang,1,2 Hua Fan,3 Yong Xu,4 Kerang Zhang,4 Xuezhu Huang,1 Yan Zhu,1 Manqiu Sui,1
Gaoxiang Sun,1 Kun Feng,1 Bo Xu,1 Xiaoqian Zhang,1 Zhonghua Su,5 Chunqing Peng,6 and Pozi Liu1*
1
Department of Psychiatry, Tsinghua University Yuquan Hospital, Beijing, China
Institute of Mental Health, Peking University, Beijing, China
2
3
Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing, China
4
Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China
Second Affiliated Hospital of Jining Medical College, Jining, China
5
6
Clinical Psychology Section, First Affiliated Hospital of Nanhua University, Hengyang, China
Received 19 October 2010; Accepted 25 April 2011
The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine-to-serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3),
rs6280, has been widely studied for its association with SZ, but
with conflicting results. Altered levels of DRD3 mRNA have also
been reported in SZ compared with normal controls. Moreover,
it has been suggested that DRD3 is subject to recent positive
selection in European populations. To explore the potential role
of DRD3 in SZ from these various aspects, we conducted a
threefold study. First, we tested the genetic association of rs6280
with SZ in 685 SZ patients and 768 normal controls. Second, we
examined DRD3 mRNA levels in peripheral leukocytes in a
subset of 37 patients and 37 controls. Finally, we investigated
the possible recent positive selection on DRD3 in an East Asian
population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P ¼ 0.045),
with the ancestral CC genotype being significantly over-represented in SZ patients. DRD3 mRNA levels were significantly
lower in patients than in controls (P ¼ 5.91E5). The derived Callele of rs6280 might have been subject to recent positive
selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural
selection, might be involved in vulnerability to SZ in the Han
Chinese population. These findings may further add to the body
of data implicating DRD3 as a schizophrenia risk gene.
How to Cite this Article:
Zhang F, Fan H, Xu Y, Zhang K, Huang X, Zhu
Y, Sui M, Sun G, Feng K, Xu B, Zhang X, Su Z,
Peng C, Liu P. 2011. Converging Evidence
Implicates the Dopamine D3 Receptor Gene
in Vulnerability to Schizophrenia.
Am J Med Genet Part B 156:613–619.
initially proposed as a risk gene because the dopamine D3 receptor
binds antipsychotic drugs and is abundant in the limbic system of
the brain. Furthermore, DRD3 maps to chromosome 3q13.3, which
some linkage analyses have suggested as a region of susceptibility to
SZ [Kaneko et al., 2007]. Therefore, DRD3 is considered a promising functional and positional candidate gene for SZ.
One of the most extensively investigated polymorphisms within
this gene is the single nucleotide polymorphism (SNP) rs6280
(Ser9Gly) in exon 2, resulting in a serine (Ser) to glycine (Gly)
substitution at codon 9. Some studies suggested an association of
the Ser allele [Ishiguro et al., 2000], the Gly allele [Kennedy et al.,
1995], or homozygotes of both types [Crocq et al., 1992; Williams
et al., 1998] with SZ. However, other studies failed to detect a
positive association for this marker, in agreement with two recent
2011 Wiley-Liss, Inc.
Key words: schizophrenia; DRD3; rs6280; positive selection
INTRODUCTION
Schizophrenia (SZ) is a severe mental disorder, with a heritability as
high as 80%. Dopamine signaling is strongly implicated in the
pathophysiology of SZ, thus dopaminergic genes have received
much attention in the search for the genetic basis of the disorder.
Among them is the dopamine D3 receptor gene (DRD3), which was
2011 Wiley-Liss, Inc.
Grant sponsor: National Natural Science Foundation of China; Grant
numbers: 30570430, 81000583, 81000578; Grant sponsor: Tsinghua YuYuan Medical Sciences Fund; Grant number: 20240000518.
Fuquan Zhang, Hua Fan, and Yong Xu contributed equally to this work.
*Correspondence to:
Pozi Liu, Department of Psychiatry, Tsinghua University Yuquan Hospital,
5 Shijingshan Road, Beijing 100049, China.
E-mail: liupozi@tsinghua.edu.cn
Published online 18 May 2011 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/ajmg.b.31203
613
614
meta-analyses [Allen et al., 2008; Ma et al., 2008]. Thus, the
correlation between DRD3 and SZ remains controversial, and has
yet to be further verified.
In line with the concept that abnormal levels of mRNA and
proteins in the brain might be involved in the etiology of SZ
[Iwamoto and Kato, 2006], postmortem studies have revealed
changes in mRNA and protein levels of DRD3 in the brain of SZ
patients [Schmauss et al., 1993; Gurevich et al., 1997; MeadorWoodruff et al., 1997]. On the other hand, Ilani et al. [2001]
suggested increased levels of DRD3 mRNA in blood lymphocytes
of SZ, while Vogel et al. [2004] reported the downregulation of
DRD3 mRNA in SZ. Hence, the significance of changes of DRD3
mRNA in peripheral leukocytes in SZ is inconclusive because of the
limited number of such studies. Thus, further evidence is also
needed in this regard.
The notion that alleles increasing disease risk are new mutations
(i.e., derived alleles) has been broadly accepted for Mendelian
diseases and more or less explicitly extended to common diseases.
However, some susceptibility polymorphisms for common diseases
ostensibly deviate from this paradigm, in that the alleles increasing
risk are ancestral ones, while derived alleles are protective. Recently,
the ancestral susceptibility model proposed that the ancestral alleles
adapted to past environments may be poorly adapted to new
environments associated with the shift in lifestyle of human populations, thus giving rise to an increased risk of some common
diseases [Di Rienzo and Hudson, 2005]. Therefore, analyses of
functional candidate genes undergoing recent natural selection may
derive new common susceptibility (or protective) alleles for human
phenotypes. It has been suggested that a common haplotype of
DRD3 affected by recent positive selection is associated with
protection from SZ in a European population, and that the selection
acts most probably on rs6280 [Costas et al., 2009]. However, it
remains unknown whether such selective pressure acts on Asian
populations.
In this work, we tested the genetic association of rs6280 with SZ,
investigated changes of DRD3 mRNA expression in blood leukocytes, and explored the possible natural selection on rs6280 within
an East Asian population.
MATERIALS AND METHODS
Subjects
The patient group comprised 685 patients with SZ, with a mean age
of 30.65 10.24 years ranging from 15 to 70 years. The patients
were recruited through clinical settings during the period between
March 2006 and February 2008. Clinical diagnosis was made by at
least two consultant psychiatrists according to the Diagnostic and
Statistical Manual of Mental Disorders Fourth Edition (DSM-IV)
criteria for SZ. All patients recruited for this study were also assessed
with the Chinese Version of the Modified Structured Clinical
Interview for DSM-IV TR Axis I Disorders Patient Edition
(SCID-I/P, 11/2002 revision). We excluded potential participants
who were pregnant or had significant medical conditions, unstable
psychiatric features (e.g., suicidal) or a history of substance abuse or
drug addiction within the previous 6 months, with the exception of
nicotine dependence.
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
The control group consisted of 768 healthy volunteers aged
28.13 8.01 years ranging from 16 to 60 years. They were recruited
from local communities or were people undergoing routine health
checkups. All control subjects were assessed using the SCID. Subjects with relevant physical diseases or a history of major psychiatric
disorders or suicidal behavior were excluded, and those who had a
first-degree relative with a history of severe mental disorder or
suicidal behavior were also excluded.
Of the above subjects, 37 first episode medication-free patients
and 37 healthy controls were used to measure expression levels of
DRD3 mRNA.
All the subjects were Chinese of Han origin and came from the
same geographical areas in Northern China. They all gave written
informed consent for this study as approved by the Ethical Committee for Medicine of the First Hospital of Shanxi Medical
University, China.
For natural selection analysis, we downloaded the phasing data
from the release two of the phase 3 of the International HapMap
Map (HapMap3_r2) genotype data [Frazer et al., 2007], comprising
358 individuals from three populations: 170 Asians from Japanese
in Tokyo of Japan and Han Chinese in Beijing of China (ASN), 100
Yoruba in Ibadan, Nigeria (YRI), and 88 Utah residents with
ancestry from northern and western Europe (CEU).
Sequencing and Genotyping
PCR was performed to amplify the polymorphisms. The primer
pairs for the polymorphism comprised the forward primer 50 ATACGCACAATCTTCACCCG-30 and the reverse primer 50 ATACCACCCAGGGCATCA-30 . The PCR products were sequenced using an ABI 3730 DNA sequencer, as previously described
[Fan et al., 2010].
Quantitative Reverse Transcriptase PCR
(qRT-PCR)
A 3-ml peripheral blood sample was taken from each of a subset of
37 control subjects and 37 patients. The patients were all first
diagnosed with no prior psycholeptic treatment. The leukocytes
were isolated by centrifugation from the fresh blood sample. Total
RNA was extracted from leukocytes with Trizol (Invitrogen, Carlsbad, CA) according to the manufacture’s instruction. The purity
and integrity of total RNA were evaluated by ultraviolet spectrometric measurements and denaturing agarose gel electrophoresis,
respectively. Expression of the glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) was used as an internal control. Expression of DRD3 messenger RNA (mRNA) was measured by relative
quantitative analysis using the ABI PRISM 7500 real-time PCR
(RT-PCR) system (Applied Biosystems, Foster City, CA). A 20 ml
reaction volume containing 10 ml of 2 SYBR Green Mastermix
(Applied Biosystems), 1 ml of mixed primers (5 mmol/L), and 2 ml of
cDNA was used for RT-PCR amplification. All RT-PCR reactions
were performed in triplicate. The primers used for real-time PCR
included 50 -GGCACATCTGGAGCTGAAG-30 (forward) and 50 CCTCTCTTTTCAACTCTCCTCCT-30 (reverse). The detailed RTPCR conditions comprised 95 C for 10 min, followed by 40 cycles of
95 C for 15 sec and 60 C for 1 min.
ZHANG ET AL.
615
The comparative Ct (2DDCt ) method was used for quantification
of transcripts. Efficiencies of cDNA amplification of DRD3 and
GAPDH were approximately equal. Relative expression of DRD3
mRNA was calculated by normalization with GAPDH gene
expression.
Statistical Analysis
Allelic and genotypic associations were analyzed with PLINK v1.07
[Purcell et al., 2007]. The differences of mRNA levels between
the patients and the controls were analyzed by the Mann–Whitney
U-test (two-tailed) using SPSS for Windows (version 17.0). The
P-value was set at 0.05 for significance levels.
Natural selection was analyzed using the Sweep program [Sabeti
et al., 2002]. It uses the long range haplotype (LRH) test to look for
alleles of high frequency with long-range linkage disequilibrium
(LD), which suggest the haplotype rapidly rose to high frequency
before recombination could break down associations with nearby
markers [Sabeti et al., 2002]. All the core haplotypes around DRD3
were identified. For each haplotype at each block (i.e., the core
haplotype), we calculated the extended haplotype homozygosity
(EHH). EHH is the probability that two randomly chosen chromosomes carrying the core haplotype of interest are identical by
descent for the entire interval from the core region to a specified
distance. We also calculated the relative EHH (rEHH), the factor by
which EHH decay on the tested core haplotype compared with the
decay of EHH on all other core haplotypes combined [Sabeti et al.,
2002]. In doing so, the influence of different recombination rates
along the genome in EHH was corrected using the other haplotypes
of the same region. Moreover, it employed another algorithm, cross
population EHH (XP-EHH), to detect selective sweeps in which the
selected allele has approached or achieved fixation in one population but remains polymorphic in the human population as a whole
[Sabeti et al., 2007].
RESULTS
Genetic Association
The genotypic distributions of rs6280 did not deviate from
the Hardy–Weinberg equilibrium (P > 0.01) in either the
patient or control group. As can be seen in Table I, genotypic
distributions of the SNP were significantly associated with SZ
(P ¼ 0.045). The frequency of the rs6280 CC genotype was significantly higher in the patients (CC vs. TT þ TC) than in the controls
(P ¼ 0.028). However, no significant allelic association was
observed.
Expression of DRD3 mRNA
qRT-PCR analysis showed that the expression of DRD3 in peripheral leukocytes was significantly lower in the patients (DCt ¼
5.00 8.79, n ¼ 37) than in the controls (DCt ¼ 3.77 3.06,
n ¼ 37) (P ¼ 5.91E5). There was no correlation between the
expression of DRD3 and the genotypic or allelic frequency of rs6280
(data not shown).
Natural Selection Analysis
We detected a 16-marker haplotype core in the 170 individuals from
ASN, encompassing rs226083, rs167770, rs226082, rs324029,
rs6810284, rs10934256, rs6806217, rs324024, rs16822416,
rs3732783, rs6280, rs324026, rs7638876, rs7638961, rs9825563, and
rs6769975. There were three major core haplotypes, CH1
(GATGGCAAGTTTTTAC), CH2 (GGCAGAAAGTCCCCGC),
and CH3 (GGCAGAAAGTCCCCAC), with a frequency of 0.65,
0.25, and 0.02, respectively. Thus, CH1 was the proxy of the rs6280 T
allele, and CH2 of the rs6280 C allele. As can be seen in Figure 1, our
data did not support the existence of natural selection on these core
haplotypes within ASN (P > 0.05). However, the allele frequency of
rs6280 varies largely across the world (Fig. 2). Therefore, XP-EHH
was employed to detect the signal of natural selection among ASN,
CEU, and YRI. The results showed the existence of natural selection
on rs6280 between ASN and YRI (P < 0.001), and between CEU and
YRI (P < 0.001), but not between ASN and CEU (P ¼ 0.188)
(Table II).
DISCUSSION
The dopamine D3 receptor has long been thought to be involved in
the pathogenesis of SZ because of its preferential expression in the
limbic areas of the brain, which are associated with various aspects
of behavior, emotion, and cognition, as well as its strong affinity to
antipsychotic drugs. Of particular interest in SZ is the non-synonymous SNP rs6280, which has been related to altered dopamine
binding affinity [Lundstrom and Turpin, 1996]. The dopaminemediated cAMP response is increased with the Gly variant, and the
mitogen-associated protein kinase signal is prolonged compared
with the Ser variant [Jeanneteau et al., 2006]. The present study
detected a significant over-representation of the rs6280 Gly/Gly
(CC at the DNA level) genotype in SZ compared with the controls,
consistent with a recent study from Japan in terms of association
direction [Utsunomiya et al., 2008]. Intriguingly, our observation
that rs6280 Gly/Gly carriers had a higher risk of developing SZ,
resonates with a cognitive function study indicating that rs6280
TABLE I. Association Analyses of rs6280 Between SZ Patients and Controls
CTL
SZ
n
768
685
TT (freq.)
377 (0.491)
345 (0.504)
CTL, controls; freq., frequency.
TC (freq.)
341 (0.444)
274 (0.400)
CC (freq.)
50 (0.065)
66 (0.096)
P (df ¼ 2)
0.045
T
1095 (0.713)
964 (0.704)
C
441 (0.287)
406 (0.296)
P (df ¼ 1)
0.584
OR (95%CI)
1.05 (0.89–1.23)
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
616
FIG. 1. Haplotype bifurcation diagrams for each haplotype in the ASN population. A 16-marker haplotype core was detected, and these 16 SNPs
defined core haplotypes (denoted CH1–3). Panels 1, 2, and 3 denote CH1, CH2, and CH3, respectively. The core haplotype CH1 carried the rs6280
Tallele, where as CH2 and CH3 carried the rs6280 C allele. CH3 was very rare; thus CH2 was chosen as the proxy of the rs6280 C allele. There was no
predominance of one thick branch in each of the haplotype bifurcation diagrams, which would indicate a long-range LD, and correspondingly high
EHH.
could affect executive functions in healthy and first-episode psychosis adolescents, with the Gly/Gly subjects showing poorer
performance than the Ser/Ser individuals [Bombin et al., 2008].
Therefore, it is tempting to speculate that rs6280 might affect
disease susceptibility through its influence on cognition.
DRD3 mRNA levels were significantly higher in the controls than
in the medication-free patients, suggesting that the alteration of
DRD3 mRNA expression was not due to medication, but may be
attributable to the disease process itself. This result was in keeping
with a previous finding [Vogel et al., 2004]. Owing to the limited
mRNA samples and the rarity of the minor genotype of rs6280 in
our sample, our data did not support a correlation between the
altered mRNA levels and the rs6280 genotypes. Nevertheless, the
result did suggest the involvement of DRD3 in risk of SZ, although
the mechanism underlying the down-regulation of DRD3 in SZ
requires further exploration.
Detecting recent natural selection would have valuable implications for the study of human diseases. Using Sweep, we sought to
explore the genetic imprint of recent positive selection by applying
the LRH test to the HapMap Asian samples. Core haplotypes that
FIG. 2. Global distribution of rs6280. Worldwide allele-frequency distribution for candidate polymorphisms provide evidence for selection.
The rs6280 C is common in Africa, but T is common in Africa, but T is common among most areas elsewhere.
ZHANG ET AL.
617
TABLE II. XP-EHH Among ASN, CEU, and YRI
ASN vs. CEU
ASN vs. YRI
CEU vs. YRI
FST
9.30E04
0.293
0.240
Contingency, x2
1.737
159.004
91.088
P-value
0.188
<0.001
<0.001
with more genotyped markers, are warranted to clarify the role of
DRD3 in SZ.
In conclusion, the evidence presented in this study suggests that
DRD3 might be involved in vulnerability to SZ in the Han Chinese
population, and the ancestral susceptibility of this gene may result
from the actions of natural selection.
ACKNOWLEDGMENTS
show unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the
human gene pool faster than expected under neutral evolution. The
more powerful algorithm XP-EHH uses cross-population comparison of haplotype lengths with control for local variation in
recombination rates. Although we failed to detect natural selection
in ASN by LRH, pairwise comparisons among the three populations
revealed the presence of a selective sweep on rs6280. The prominent
difference detected here was between Africa and elsewhere, rather
than between Europe and Asia. Since YRI is more ‘‘ancient’’ than
other populations and thus represents the ‘‘ancestral’’ one, the
rising of the rs6280 T allele frequency in ASN and CEU supports the
positive selection of rs6280 in these two populations. Costas et al.
[2009] suggested that a haplotype containing the derived allele Ser
(T at the DNA level) at rs6280 has been under recent positive
selection in European populations, leading to its fast increase in
frequency, and that rs6280 is most probably the actual polymorphism subject to selection at this haplotype. However, unlike Costas
et al. [2009], we failed to find a significant selective sweep on DRD3
within ASN, possibly because of the limited sample size in our study
or population stratifications across studies. This work may just
scratch the surface of natural selection on DRD3; such an endeavor
should be enhanced by the generation of expanded data sets.
It must be borne in mind that the selective pressure on DRD3
detected herein may not necessarily target the disease phenotype per
se, but rather phenotypes resulting from normal biological processes, such as cognition [Laszy et al., 2005; Bombin et al., 2008] or
sodium homeostasis [Asico et al., 1998]. Notably, some other SZ
candidate genes may be undergoing recent adaptive selection, such
as MAOB [Carrera et al., 2009] and GARBRB2 [Lo et al., 2007],
which also fit the ancestral susceptibility model. Such genes may
provoke another interesting area in the genetic study of human
phenotypes, by broadening one’s view of diseases from a virtually
static point into a dynamic one which will take the long history and
thereby the evolutionary force into consideration.
Although we present convergent evidence from various facets to
support a role of DRD3 in SZ, the results of our work must be
evaluated with caution and viewed in the context of several potential limitations. First, although the tested marker is probably one of
the most vital functional loci in DRD3, the action of this gene is far
from being fully explained by this single marker, and the significance level of 0.045 would not survive a multiple testing correction.
Second, the effect size of this polymorphism was quite small. In
addition, assuming an odds ratio (OR) being 1.1, the statistical
power of 685 cases and 768 controls was relatively low (11.9%)
[Dupont and Plummer, 1998]. Therefore, larger studies, preferably
We would sincerely thank the patients, their families and the
healthy volunteers for their participation, and all the medical staff
involved in specimen collecting. This work was supported by
National Natural Science Foundation of China (30570430,
81000583, and 81000578), and Tsinghua Yu-Yuan Medical Sciences
Fund (20240000518). We thank Chunyu Liu for his valuable
suggestion.
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