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. 2017 Nov 23;13:2855–2865. doi: 10.2147/NDT.S152784

No association between dopamine D3 receptor gene Ser9Gly polymorphism (rs6280) and risk of schizophrenia: an updated meta-analysis

Xing-ling Qi 1, Jin-feng Xuan 1, Jia-xin Xing 1, Bao-jie Wang 1, Jun Yao 1,✉
PMCID: PMC5703163  PMID: 29200860

Abstract

Objective

Ser9Gly (rs6280) is a functional single-nucleotide polymorphism (SNP) in the dopamine receptor D3 (DRD3) gene that may be associated with schizophrenia. We performed a meta-analysis to determine whether Ser9Gly influences the risk of schizophrenia and examined the relationship between the Ser9Gly SNP and the etiology of schizophrenia.

Methods

Case–control studies were retrieved from literature databases in accordance with established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between Ser9Gly and schizophrenia. Subgroup analysis and sensitivity analysis were also performed.

Results

Seventy-three studies comprising 10,634 patients with schizophrenia (cases) and 11,258 controls were included in this meta-analysis. Summary results indicated no association between Ser9Gly and risk of schizophrenia. In the dominant genetic model, the pooled OR using a random effects model was 0.950 (95% CI, 0.847–1.064; P=0.374).

Conclusion

Results of this meta-analysis suggest that the Ser9Gly SNP is not associated with schizophrenia. These data provide possible avenues for future case–control studies related to schizophrenia.

Keywords: dopamine receptor D3, schizophrenia, meta-analysis, gene polymorphism

Introduction

Schizophrenia is a common mental disorder caused by synergic effects of multiple genetic and environmental factors.1 Heritability of up to 80% has been reported for schizophrenia;4 however, the precise etiology of this disease remains inconclusive.2,3 Results of several genome-wide linkage and association studies have indicated genes and chromosomal regions associated with susceptibility to schizophrenia.5,6 Several investigators have suggested that dysregulated dopaminergic neurotransmission has a role in the pathogenesis of schizophrenia.7–10 Dopamine functions as a neurotransmitter by binding to dopamine receptors on the postsynaptic membrane and autoreceptors on the presynaptic membrane.

Dopamine receptor D3 (DRD3) is a candidate gene for evaluating an association between dopaminergic neurotransmission and schizophrenia risk. DRD3 is located on chromosome 3 in the q13.3 band and has 52% global homology with the D2 receptor band. DRD3 is primarily expressed in the limbic areas of the human brain11 and contributes emotional, cognitive, and endocrine functions.12 A single-nucleotide polymorphism (SNP) in the first exon of DRD3 corresponds to a serine-to-glycine substitution at position 9 in the extracellular N-terminal domain of the polypeptide (ie, Ser9Gly [rs6280]). Ser9Gly is a functional SNP that yields a protein with altered dopamine-binding affinity.13 The substitution of serine with glycine is thought to yield D3 autoreceptors with a higher affinity for dopamine and more robust intracellular signaling.14 Other authors have associated Ser9Gly with acute pain in sickle cell disease, bipolar disorder, Parkinson’s disease, and suicidal behaviors.15–18

In recent years, numerous molecular epidemiological studies have addressed the association between Ser9Gly and schizophrenia risk. However, some investigators determined that Ser9Gly was associated with the disease,19,20 whereas others found no association.21–23 These inconclusive and discordant findings have been attributed to small sample size, inclusion of various genetic backgrounds, and potential confounding bias.24

Meta-analysis has been applied widely as a statistical method in medical studies, particularly for topics that are studied extensively yet yield controversial results.25 Utsunomiya et al conducted a meta-analysis in 2008 to evaluate the association between Ser9Gly and schizophrenia.26 Their pooled results of 9 case–control studies indicated that Ser9Gly was unlikely to confer susceptibility to schizophrenia in the Japanese population.26 In a second meta-analysis conducted in 2008, results involving 51 case–control studies indicated no association of Ser9Gly with schizophrenia.21 In the years since these meta-analyses were completed, additional molecular epidemiological studies have addressed the roles of Ser9Gly in the occurrence of schizophrenia in various populations. Herein, we describe an updated meta-analysis of studies involving associations between DRD3 polymorphisms and schizophrenia.

Methods

Identification of relevant studies

To identify studies eligible for inclusion in this meta-analysis, 3 online electronic English databases (PubMed, Embase, and Web of Science) and 1 online Chinese database (CNKI) were searched. The most recent search was conducted in July 2017. The following key words were used for study identification: DRD3, dopamine receptor 3, dopamine D3 receptor, dopamine receptor D3, schizophrenia, polymorphism, and Ser9Gly. Reference lists of the accessed articles and of potentially relevant review articles were screened to identify additional studies.

The following inclusion criteria were applied: 1) case–control design; 2) inclusion of patients with schizophrenia; and 3) statement of allele or genotype frequencies. For studies in which the same or overlapping data were reported by the same authors, the most recent article was selected. Excluded from the meta-analysis were studies 1) without a control population, 2) that duplicated an earlier publication, and 3) that lacked data regarding genotype frequency. Study authors were queried via e-mail for additional study details, such as allele or genotype frequencies or sample characteristics, when these data were not provided in the article.

Data extraction

Two reviewers independently extracted information from all eligible publications. Disagreements were resolved by discussion until the 2 reviewers reached consensus. The following details of each article were recorded: first author’s last name, publication year, sample size, region, and number of genotypes for cases and controls. To detect potentially moderating influences on the effects findings reported in the case–control studies, we also included the following variables: 1) ethnicity of the sample population; 2) source of controls; 3) mean age of the control group; 4) diagnostic criteria; and 5) gender index.

Statistical analysis

Stata version 10.0 (Stata Corp., College Station, TX, USA) was applied for statistical analysis. Hardy–Weinberg equilibrium (HWE) was determined for the genotype distribution of controls, and the chi-square goodness-of-fit test was performed to ascertain deviations from HWE. The Thakkinstian method was applied for pooled frequency analysis, as described previously.27 All statistical tests were 2-tailed, and significance was defined as P<0.05.

Odds ratios (ORs) with accompanying 95% confidence intervals (CIs) were calculated to assess the strength of the association of Ser9Gly and schizophrenia. Pooled effect sizes among the included articles were examined with a random effects model, which accounts for heterogeneity among the studies and yields the likely effect size across populations. We did not apply a fixed effects model because we wanted to avoid the assumption that patients were being sampled from a single population. In the fixed effects model, the effect size could be biased by heterogeneity among studies.28

Three genetic models were applied to determine overall pooled ORs: the allele contrast model, the dominant model, and the recessive model. As previously described, OR1 (AA vs aa), OR2 (Aa vs aa), and OR3 (AA vs Aa) were compared, with A defined as the risk allele.25 The most suitable genetic model was ascertained from these pairwise differences. Specifically, for OR1 = OR3 ≠1 and OR2 =1, the recessive model was selected (OR =1 means P>0.05; OR ≠1 means P<0.05). For OR1 = OR2 ≠1 and OR3 =1, the dominant model was considered. For OR2 =1/OR3 ≠1 and OR1 =1, the complete-overdominant model was presumed. Lastly, for OR1>OR2>1 and OR1>OR3>1 (or OR1<OR2<1 and OR1<OR3<1), the data were evaluated in the context of the codominant model.29

The degree of heterogeneity between studies was determined by means of the Q statistic.30,31 Specifically, P>0.05 by the Q test indicated the absence of heterogeneity, and P<0.05 indicated heterogeneity. I2 was defined as the proportion of observed variance in effect sizes attributable to true differences among studies. Conventional interpretations of I2 include limits for low (<25%), moderate (approximately 50%), and high (>75%) heterogeneity.32 Subgroup analysis was carried out by ethnicity (ie, East Asian, Caucasian, and other populations) and by source of controls (ie, hospital-based and population-based).

Publication bias was evaluated by visual inspection of a funnel plot in which the standard error of log(OR) of each study was plotted against its log(OR). An asymmetric plot implied possible publication bias, and the degree of asymmetry was calculated by means of Egger’s test. P<0.05 indicated significant publication bias.33

Sensitivity analysis was performed to assess the potential influence of a single study on the pooled effect size. Specifically, each study was omitted singly from the meta-analysis, and significant alterations to the pooled effect size were ascertained.

Results

A total of 155 articles were identified by database searches. After removing duplicate or overlapping articles and those that did not fulfill the inclusion criteria, 60 publications were included in the meta-analysis.12,19–23,26,34–85 These articles included 73 individual studies that comprised 10,634 patients with schizophrenia (ie, cases) and 11,258 unaffected participants (ie, controls). Patients of diverse races and ethnicities were included (eg, East Asian, Caucasian, Latino, and Indian). The mean age of the controls ranged from 25.0 to 53.0 years. The key characteristics of the studies are summarized in Table 1. Genotype and allele frequencies, and details regarding HWE are presented in Table 2. For Ser9Gly, the total numbers of Ser/Ser, Ser/Gly, and Gly/Gly genotypes were 5,532, 5,117, and 1,900 for cases and 5,173, 5,066, and 1,022 for controls, respectively. Of the 73 studies, 4 studies deviated significantly from HWE.

Table 1.

Baseline characteristics of qualified studies in this meta-analysis

References Year Location Ethnicity Controls source Mean age of control group Diagnostic criteria Gender index (case) Gender index (control)
Crocq et al19 1992 France Caucasian Hospital-based 33.9 DSM-III-R 0.38 –
Crocq et al19 1992 UK Caucasian Population-based 45.9 DSM-III-R 0.58 0.74
Yang et al61 1993 China East Asians Population-based 25.05 RDC 0.49 0.56
Nanko et al64 1993 Japan East Asians Population-based 27.8 DSM-III-R 0.82 0.91
Jönsson et al67 1993 Sweden Caucasian Population-based 39 DSM-III-R 0.46 0.61
Nöthen et al72 1993 Germany Caucasian Population-based – – – –
Nöthen et al73 1993 Germany Caucasian Population-based 28.2 DSM-III-R 0.5 0.88
Laurent et al45 1994 France Caucasian Population-based 48 DSM-III-R 0.38 0.72
Saha et al53 1994 Singapore East Asians Population-based 38 ICD-9 – –
Mant et al65 1994 UK Caucasian Population-based 46.6 DSM-III-R 0.74 0.8
Kennedy et al66 1995 North America Caucasian Hospital-based – DSM-III-R – –
Kennedy et al66 1995 Italy Caucasian Hospital-based – DSM-III-R – –
Inada et al81 1995 Japan East Asians Population-based 54 – 1.09 1
Durany et al38 1996 Spain Caucasian Population-based 53 ICD-10 1.38 1.44
Gaitonde et al41 1996 UK Caucasian Hospital-based 41.7 ND 0.83 0.93
Ohara et al50 1996 Japan East Asians Population-based 34.4 DSM-IV – 1.37
Rietschel et al51 1996 Germany Caucasian Population-based 30.2 DSM-III-R 0.66 0.96
Shaikh et al54 1996 UK Caucasian Hospital-based – DSM-III-R – –
Tanaka et al59 1996 Japan East Asians Population-based 42.7 DSM-III-R 0.92 0.41
Nimgaonkar et al20 1996 USA African-American Hospital-based – DSM-III-R 1.24 1.33
Nimgaonkar et al20 1996 USA Caucasian Hospital-based – DSM-III-R 0.67 1.1
Chen et al22 1997 China East Asians Hospital-based 45 DSM-III-R 0.86 1.13
Ebstein et al39 1997 Italy Caucasian Population-based 36.5 DSM-III-R 0.31 1.03
Ebstein et al39 1997 Israel Ashkenazi Population-based 32.9 DSM-III-R – 0.94
Ebstein et al39 1997 Israel Non-Ashkenazi Population-based 32.9 DSM-III-R – 0.94
Maziade et al48 1997 Canada Caucasian Population-based – DSM-III-R 0.46 –
Hawi et al42 1998 Ireland Caucasian Population-based – DSM-III-R 0.47 0.79
Krebs et al92 1998 France Caucasian Population-based 35.47 DSM-III-R 0.62 1
Spurlock et al56 1998 Ireland Caucasian Population-based – DSM-III-R – –
Spurlock et al56 1998 Northern
Sweden		 Caucasian Population-based – DSM-III-R – –
Spurlock et al56 1998 Portugal Caucasian Population-based – DSM-III-R – –
Spurlock et al56 1998 Wales Caucasian Population-based – DSM-III-R – –
Spurlock et al56 1998 Austria Caucasian Population-based – DSM-III-R – –
Spurlock et al56 1998 France Caucasian Population-based – DSM-III-R – –
Ishiguro et al43 2000 Japan East Asians Population-based 47.2 DSM-III-R or ICD-10 0.74 1.07
Ishiguro et al43 2000 Japan East Asians Population-based 48.5 DSM-III-R or ICD-11 0.9 0.81
Joober et al44 2000 Canada Caucasian Hospital-based – DSM-IV – –
Meszaros et al49 2000 Austria Caucasian Population-based – DSM-III-R – –
Sivagnanasundaram et al55 2000 UK Caucasian Population-based – DSM-III-R – –
Hauser et al77 2000 Poland Caucasian Population-based 28.76 DSM-IV – –
Cordeiro et al37 2001 Brazil Latinos Population-based – ICD-10 – –
Løvlie et al47 2001 India Indians Population-based 43 DSM-IV – 0.83
Rybakowski et al52 2001 Poland Caucasian Population-based 27 DSM-IV, ICD-10 0.61 1.13
Anney et al35 2002 UK and Ireland Caucasian Population-based 43 DSM-IV 0.28 0.28
Ventriglia et al60 2002 Italy Caucasian Population-based – DSM-IV – –
Morimoto et al62 2002 Japan East Asians Population-based – ICD-10 1.14 –
Zhao et al83 2002 China East Asians Population-based 55.9 DSM-III-R 0.83 1.4
Tang et al84 2002 China East Asians Population-based 33 CCMD-II-R 0.76 1.06
Jönsson et al71 2003 Sweden Caucasian Population-based – DSM-III-R – –
Iwata et al76 2003 Japan East Asians Population-based – DSM-IV – –
Baritaki et al36 2004 Greece Caucasian Population-based 45.1 DSM-IV 0.7 0.63
Jönsson et al63 2004 Germany Caucasian Population-based 30.2 DSM-IV 0.85 0.25
A et al82 2004 China East Asians Population-based – – 0.63 –
Staddon et al57 2005 Northern Spain Basque Population-based – DSM-IV 0.54 1
Yang93 2005 China East Asians Population-based 35.04 DSM-IV 1.12 1.09
Liang94 2005 China East Asians Population-based 25 DSM-IV, CCMD-3 0.98 0.98
Talkowski et al58 2006 USA Caucasian Population-based – DSM-IV – –
Yi et al85 2006 China East Asians Population-based 35 DSM-IV 1.12 1.13
Ma et al21 2008 China East Asians Hospital-based 35.02 DSM-IV 0.62 0.81
Lorenzo et al46 2007 Spain Caucasian Population-based – DSM-IV – –
Chang et al68 2007 China East Asians Population-based – DSM-IV – –
Güzey et al34 2007 Italy Caucasian Population-based – DSM-IV 0.2 0.17
Fathalli et al40 2008 Canada, Tunisia, and Hungary Caucasian Hospital-based – DSM-III-R or DSM-IV 0.37 0.85
Utsunomiya et al26 2008 Japan East Asians Population-based 55 DSM-IV 0.92 0.92
Krelling et al78 2008 Brazil Latinos Population-based 40.27 – – –
Barlas et al23 2009 Turkey Caucasian Population-based 31.7 DSM-IV 0.21 0.23
Zai et al69 2010 Europe Caucasian Population-based – DSM-IV 0.57 0.42
Sáiz et al75 2010 Asturia, Northern Spain Caucasian Population-based 40.6 DSM-IV 0.66 0.95
Nunokawa et al80 2010 Japan East Asians Population-based 38.1 DSM-IV 0.9 0.92
Zhang et al70 2011 China East Asians Population-based 28.13 DSM-IV – –
Tee et al74 2011 Malaysia East Asians Population-based 38.4 – 0.91 0.83
Zheng et al79 2012 China East Asians Population-based 33.1 DSM-IV 0.69 0.72
Yang et al12 2016 China East Asians Population-based 42 DSM-IV – –
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Notes: Gender index = (female/male). En dashes indicate data not available.

Abbreviations: DSM, Diagnostic and Statistical Manual of Mental Disorders; RDC, Research Diagnostic Criteria; ICD, International Classification of Diseases; ND, not determined; CCMD, Chinese Classification of Mental Disorders.

Table 2.

Distribution of genotype and allele frequencies of the DRD3 Ser9Gly polymorphism

References Genotype distribution
PHWE Allele frequency
Cases, n
Controls, n
Cases, %
Controls, %
Ser/Ser Ser/Gly Gly/Gly Ser/Ser Ser/Gly Gly/Gly Ser Gly Ser Gly
Crocq et al19 37 26 10 134 128 24 0.3930 68 32 69 31
Crocq et al19 37 18 13 170 153 41 0.4616 67 33 68 32
Yang et al61 54 45 8 56 95 24 0.1630 65 35 59 41
Nanko et al64 48 35 8 50 40 10 0.6300 72 28 70 30
Jönsson et al67 34 36 6 63 83 37 0.3154 60 40 55 45
Nöthen et al72 31 22 7 26 41 4 0.0193 68 32 65 35
Nöthen et al73 20 26 14 25 34 9 0.6289 68 32 62 38
Laurent et al45 35 33 8 43 47 10 0.5832 70 30 67 33
Saha et al53 62 66 9 34 25 4 0.8341 66 34 74 26
Mant et al65 33 23 10 62 41 6 0.8178 77 23 76 24
Kennedy et al66 37 62 18 12 14 1 0.2059 61 39 70 30
Kennedy et al66 42 43 12 73 84 15 0.1807 63 37 67 33
Inada et al81 66 40 7 34 33 10 0.6569 67 33 66 34
Durany et al38 53 43 11 92 119 24 0.1064 64 36 64 36
Gaitonde et al41 34 45 5 56 51 15 0.5255 75 25 67 33
Ohara et al50 1 152 0 59 58 15 0.8961 77 23 67 33
Rietschel et al51 61 71 14 42 43 4 0.0865 65 35 71 29
Shaikh et al54 33 56 20 20 27 5 0.3386 65 35 64 36
Tanaka et al59 54 38 8 37 40 9 0.707 69 31 66 34
Nimgaonkar et al20 30 22 13 51 66 15 0.3559 67 33 64 36
Nimgaonkar et al20 33 26 6 5 13 4 0.3874 54 46 52 48
Chen et al22 89 77 12 38 35 6 0.5939 78 22 70 30
Ebstein et al39 37 31 12 49 58 13 0.4951 66 34 65 35
Ebstein et al39 24 15 2 3 118 0 – 75 25 76 24
Ebstein et al39 20 16 10 49 42 9 1 66 34 70 30
Maziade et al48 41 27 2 54 34 6 0.8354 69 31 76 24
Hawi et al42 83 87 28 59 57 9 0.3379 70 30 69 31
Krebs et al92 36 42 11 57 69 7 0.0163 66 34 56 44
Spurlock et al56 15 16 5 25 23 8 0.4763 36 64 83 17
Spurlock et al56 25 29 13 28 49 8 0.042 64 36 62 38
Spurlock et al56 28 40 8 27 34 10 0.8928 59 41 62 38
Spurlock et al56 14 15 2 6 22 5 0.0546 63 37 51 49
Spurlock et al56 38 21 12 13 16 2 0.3137 69 31 68 32
Spurlock et al56 17 11 2 23 28 6 0.554 68 32 65 35
Ishiguro et al43 84 61 8 10 17 4 0.4375 75 25 60 40
Ishiguro et al43 61 31 7 67 77 12 0.1118 72 28 69 31
Joober et al44 44 50 12 119 127 26 0.3435 75 25 67 33
Meszaros et al49 45 35 15 52 43 5 0.2991 73 27 74 26
Sivagnanasundaram et al55 29 40 4 59 67 12 0.2476 60 40 67 33
Hauser et al77 62 58 9 50 40 8 1 71 29 71 29
Cordeiro et al37 56 57 28 19 25 4 0.2847 70 30 66 34
Løvlie et al47 16 29 11 291 242 51 0.9456 70 30 71 29
Rybakowski et al52 54 55 10 48 35 7 0.8604 72 28 73 27
Anney et al35 152 178 30 38 46 13 0.8753 67 33 63 37
Ventriglia et al60 43 51 20 88 81 19 0.9546 59 41 69 31
Morimoto et al62 23 21 4 34 26 4 0.7411 65 35 73 27
Zhao et al83 109 109 18 27 22 4 0.8681 68 32 72 28
Tang et al84 273 210 45 138 119 28 0.7518 67 33 69 31
Jönsson et al71 72 70 14 30 30 3 0.1859 63 37 71 29
Iwata et al76 73 64 9 27 30 8 0.9401 71 29 65 35
Baritaki et al36 51 46 17 70 66 27 0.098 66 34 63 37
Jönsson et al63 326 255 68 50 37 7 0.9657 70 30 73 23
A et al82 43 29 8 27 21 7 0.3735 71 29 68 32
Staddon et al57 59 40 10 278 267 51 0.2413 72 28 69 31
Yang93 35 28 7 377 341 50 0.019 70 30 71 29
Liang94 65 30 6 213 193 36 0.3993 69 31 70 30
Talkowski et al58 173 136 12 28 27 5 0.6699 70 30 69 31
Yi et al85 35 28 7 14 30 16 0.9931 55 45 48 52
Ma et al21 145 157 7 47 34 9 0.4449 72 28 71 29
Lorenzo et al46 78 82 18 66 78 13 0.1281 67 34 67 33
Chang et al68 120 105 31 115 75 8 0.3241 69 32 77 23
Güzey et al34 30 29 4 164 188 43 0.3158 62 38 65 35
Fathalli et al40 158 199 51 39 45 16 0.619 71 29 62 39
Utsunomiya et al26 120 97 29 26 15 7 0.0729 72 28 70 30
Krelling et al78 22 56 25 65 39 7 0.7251 71 30 76 24
Barlas et al23 47 37 8 15 26 20 0.2682 49 52 46 54
Zai et al69 66 82 15 177 162 24 0.1038 69 31 71 29
Sáiz et al75 103 123 39 306 243 46 0.815 71 29 72 28
Nunokawa et al80 301 239 54 28 19 1 0.2734 76 24 78 22
Zhang et al70 345 274 66 52 42 11 0.5655 79 21 70 31
Tee et al74 120 107 34 153 145 17 0.0195 69 31 72 28
Zheng et al79 133 121 26 141 89 11 0.5175 72 28 77 23
Yang et al12 459 343 78 50 37 7 0.9657 70 30 73 27
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Note: PHWE represents the P-value of Hardy–Weinberg equilibrium test in the genotype distribution of controls.

Frequency of Ser9Gly in the control population

Pooled frequencies of Ser9Gly stratified by ethnicity were determined for controls. The pooled frequency of Ser9Gly was highest among Latinos (56.8%; 95% CI, 55.9–57.6), followed by African-Americans (56.1%; 95% CI, 55.3–57.0), East Asians (38.2%; 95% CI, 35.0–41.4), Caucasians (29.0%; 95% CI, 27.7–30.4), and Indians (22.0%; 95% CI, 21.7–22.3).

Quantitative synthesis and heterogeneity analysis

Pooled ORs and corresponding 95% CIs were determined for Ser9Gly in the following genetic models: homozygous codominant, heterozygous codominant, dominant, recessive, and allele contrast (Table 3 and Figure 1). The dominant model was found to be most appropriate, according to the principles of genetic model selection.29,86 Summary results indicated no association between Ser9Gly and schizophrenia risk. In the dominant model, the pooled OR using a random effects model was 0.950 (95% CI, 0.847–1.064; P=0.374). Results of subgroup analysis by ethnicity indicated that the Ser9Gly SNP was not associated with schizophrenia among East Asians, Caucasians, or populations evaluated less frequently in the meta-analysis – such as Latino, Indian, and African-American patients (Table 4). Moreover, no association between Ser9Gly and schizophrenia was observed in subgroup analysis according to the source of controls.

Table 3.

Summarized ORs with 95% CIs for the association of DRD3 Ser9Gly polymorphism with schizophrenia

Polymorphism Genetic model n Statistical model OR 95% CI Pz I2 (%) Ph Pe
Ser9Gly Allele contrast 73 Random 0.995 0.925–1.069 0.883 28.6 0.014 0.825
Homozygous codominant 73 Random 0.914 0.759–1.102 0.346 62.3 <0.0001 0.113
Heterozygous codominant 73 Random 0.838 0.716–0.981 0.028 47.1 <0.0001 0.421
Dominant 73 Random 0.950 0.847–1.064 0.374 68.5 <0.0001 0.040
Recessive 73 Random 1.139 0.965–1.345 0.125 57.0 <0.0001 0.183
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Notes: n, number of studies; Pz, P-value for association test; Ph, P-value for heterogeneity test; Pe, P-value for publication bias test.

Abbreviations: OR, odds ratio; CI, confidence interval.

Figure 1.

Figure 1

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Forest plot of the association between the Ser9Gly polymorphism of DRD3 and schizophrenia in the dominant genetic model (Ser/Gly + Gly/Gly vs Ser/Ser).

Notes: Weights are from random effects analysis. *After the first case-control study, there was a marginally significant association between the Ser9Gly polymorphisms and schizophrenia (P=0.02). Thus, these positive findings were replicated in an additional 99 Japanese schizophrenia patients and 132 controls.43

Abbreviations: OR, odds ratio; CI, confidence interval.

Table 4.

Stratified analysis of the association of DRD3 polymorphisms with schizophrenia under dominant model

Subgroup analysis Ser9Gly
n OR 95% CI Pz I2 (%) Ph
Overall 73 0.950 0.847–1.064 0.374 68.5 <0.0001
Ethnicity
 East Asians 25 0.915 0.751–1.114 0.377 72.8 <0.0001
 Caucasians 41 0.981 0.880–1.094 0.733 36.2 0.012
 Others 7 0.862 0.368–2.017 0.732 92.2 <0.0001
Source of controls
 Hospital-based 11 1.022 0.861–1.214 0.803 4.6 0.399
 Population-based 62 0.938 0.847–1.064 0.334 72.0 <0.0001
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Notes: n, number of studies; Pz, P-value for association test; Ph, P-value for heterogeneity test. Others included the ethnicities with the rare studies, such as Latino, Indian, and African-American.

Abbreviations: OR, odds ratio; CI, confidence interval.

Sensitivity analysis

Sensitivity analysis was carried out to ascertain the contribution of each study to the overall result. Corresponding pooled ORs for analyses in which each of the 73 studies was individually removed indicated that no single study produced a significant change in the overall results of the meta-analysis. Hence, these results are stable and reliable.

Publication bias

A funnel plot was generated to assess potential publication bias (Figure 2), and a small but significant effect of publication bias was detected (Pe=0.040) (Table 3).

Figure 2.

Figure 2

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Funnel plot analysis depicting publication bias in the association between the Ser9Gly polymorphism of DRD3 and schizophrenia.

Abbreviation: OR, odds ratio.

Discussion

We conducted a meta-analysis of 73 studies (10,634 cases and 11,258 controls) to investigate the potential association of the Ser9Gly SNP in DRD3 with the occurrence of schizophrenia. Our overall findings suggest that no association exists, and results of subgroup analysis stratified by ethnicity and source of controls further validated the distribution disequilibrium of cases and controls.

Several previous meta-analyses have addressed the putative association between DRD3 polymorphisms and schizophrenia.21,26,71,80,87 In general, the results of the current meta-analysis were consistent with those published previously, with the exception of 1 meta-analysis in which DRD3 polymorphisms were found to exert a small but significant effect on schizophrenia susceptibility in Caucasian patients.87 Rather than being superfluous, our meta-analysis has several advantages over previous studies. Most importantly, our analysis involved relevant studies that have been published in the interim since the previous meta-analyses were carried out. We included 73 studies that we believe collectively represent DRD3 polymorphisms more accurately than did previous meta-analyses. In addition, we performed subgroup analyses stratified by ethnicity and source of controls to assess potential sources of heterogeneity and to test study stability. Therefore, the results of our study provide a more precise, comprehensive assertion that no association exists between Ser9Gly and schizophrenia.

Some authors have described specific ethnic groups for which associations exist between polymorphisms at certain DRD3 loci and schizophrenia. However, findings of an association of a DRD3 SNP with schizophrenia in 1 population may not be supported in another population. This phenomenon may result from 2 factors. First, different genetic backgrounds may contribute to divergence. The distribution of DRD3 allele frequencies varies among Latinos, African-Americans, East Asians, Caucasians, and Indians. Evidently, genetic liability is a high risk factor for schizophrenia.88 Gly9 allele frequencies vary almost as much in the Japanese control populations (22%–34%) as they do in northern and western Caucasian control populations (30%–44%).71 Second, patients from different populations may have disparate lifestyles and may be affected by different environmental factors.89 Epigenetic modifications that contribute to schizophrenia may be a product of transregulatory or environmental risk factors.90

The relatively small sample sizes of Latino, African-American, Indian, Ashkenazi, and non-Ashkenazi patients limited our ability to isolate stable effects for these subgroups. More studies need to be performed to explore the association between Ser9Gly polymorphism and the risk of schizophrenia in these above populations. Moreover, the lack of an association between Ser9Gly and schizophrenia was upheld when the analysis was stratified by the source of controls. However, control patients in hospital-based studies do not necessarily represent the general population, particularly when the polymorphism being evaluated is related to a disorder that affects hospital-based control patients.91 Thus, the negative results by the source of controls should be interpreted carefully. Because this Gly allele is known to alter dopamine-binding affinity, it can, to some degree, influence the function of dopamine neurotransmitter. Thus, more effort is needed to explore whether it is involved in the risk of schizophrenia.

The present study had several limitations. We observed significant heterogeneity in overall and subgroup analyses. Although we performed subgroup analysis to investigate potential sources of heterogeneity, no single factor completely accounted for this heterogeneity. Therefore, other unidentified aspects might partially contribute to heterogeneity. Second, we detected a slight but significant publication bias in the included studies. This bias can be explained, in part, by our inclusion of only English- and Chinese-language studies. Another main reason is that the negative results are not easier to publish than the positive results. Third, gene–gene interactions and epigenetics were not examined in this meta-analysis, owing to insufficient information in the included studies. By evaluating only 1 SNP in DRD3, we may have limited our analysis to a polymorphism that plays a minute role in the overall genetic influences of schizophrenia. This disorder is thought to arise from the mutual influence of multiple genes.

In summary, we found no evidence of an association between the Ser9Gly SNP in DRD3 and risk of schizophrenia. Studies involving larger sample sizes will be necessary to confirm the results of this meta-analysis – especially for certain ethnic subpopulations – and to address the epigenetic mechanisms and environmental influences that contribute to schizophrenia risk.

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (81601653) and the Doctoral Research Start Foundation of Liaoning Province (201601115) for Dr Jun Yao.

Footnotes

Author contributions

All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

References

  • 1.Hoenders R, Bartels-Velthuis A, Vollbehr N, Bruggeman R, Knechtering R, de Jong J. Natural medicines in schizophrenia: a systematic review. J Altern Complement Med. 2014;20(5):A79. [Google Scholar]
  • 2.Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363(9426):2063–2072. doi: 10.1016/S0140-6736(04)16458-1. [DOI] [PubMed] [Google Scholar]
  • 3.Heron EA, Cormican P, Donohoe G, et al. No evidence that runs of homozygosity are associated with schizophrenia in an Irish genome-wide association dataset. Schizophr Res. 2014;154(1–3):79–82. doi: 10.1016/j.schres.2014.01.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187–1192. doi: 10.1001/archpsyc.60.12.1187. [DOI] [PubMed] [Google Scholar]
  • 5.Wan CL, Zainal NZ, Lian LH, Mohamed Z. Association of the functional polymorphism in the catechol-O-methyltransferase gene with schizophrenia in the three ethnic groups of the Malaysian population. Psychiatry Res. 2011;189(1):67–71. doi: 10.1016/j.psychres.2011.02.008. [DOI] [PubMed] [Google Scholar]
  • 6.Yuan J, Jin C, Sha W, et al. A competitive PCR assay confirms the association of a copy number variation in the VIPR2 gene with schizophrenia in Han Chinese. Schizophr Res. 2014;156(1):66–70. doi: 10.1016/j.schres.2014.04.004. [DOI] [PubMed] [Google Scholar]
  • 7.Abi-Dargham A, Moore H. Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist. 2003;9(5):404–416. doi: 10.1177/1073858403252674. [DOI] [PubMed] [Google Scholar]
  • 8.Fan H, Zhang F, Xu Y, et al. An association study of DRD2 gene polymorphisms with schizophrenia in a Chinese Han population. Neurosci Lett. 2010;477(2):53–56. doi: 10.1016/j.neulet.2009.11.017. [DOI] [PubMed] [Google Scholar]
  • 9.Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III – the final common pathway. Schizophr Bull. 2009;35(3):549–562. doi: 10.1093/schbul/sbp006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Davis J, Moylan S, Harvey BH, Maes M, Berk M. Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014;48(6):512–529. doi: 10.1177/0004867414533012. [DOI] [PubMed] [Google Scholar]
  • 11.Sokoloff P, Giros B, Martres MP, et al. Localization and function of the D3 dopamine receptor. Arzneimittelforschung. 1992;42(2A):224–230. [PubMed] [Google Scholar]
  • 12.Yang B, Niu W, Chen S, et al. Association study of dopamine receptor genes polymorphisms with the risk of schizophrenia in the Han Chinese population. Psychiatry Res. 2016;245:361–364. doi: 10.1016/j.psychres.2016.08.052. [DOI] [PubMed] [Google Scholar]
  • 13.Utsunomiya K, Shinkai T, Sakata S, et al. Genetic association between the dopamine D3 receptor gene polymorphism (Ser9Gly) and tardive dyskinesia in patients with schizophrenia: a reevaluation in East Asian populations. Neurosci Lett. 2012;507(1):52–56. doi: 10.1016/j.neulet.2011.11.050. [DOI] [PubMed] [Google Scholar]
  • 14.Savitz J, Hodgkinson CA, Martin-Soelch C, et al. The functional DRD3 Ser9Gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement. PLoS One. 2013;8(1):e54108. doi: 10.1371/journal.pone.0054108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Jhun E, He Y, Yao Y, Molokie RE, Wilkie DJ, Wang ZJ. Dopamine D3 receptor Ser9Gly and catechol-o-methyltransferase Val158Met polymorphisms and acute pain in sickle cell disease. Anesth Analg. 2014;119(5):1201–1207. doi: 10.1213/ANE.0000000000000382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Chang TT, Chen SL, Chang YH, et al. The DRD3 Ser9Gly polymorphism predicted metabolic change in drug-naive patients with bipolar II disorder. Medicine (Baltimore) 2016;95(24):e3488. doi: 10.1097/MD.0000000000003488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Xu S, Liu J, Yang X, Qian Y, Xiao Q. Association of the DRD2 CAn-STR and DRD3 Ser9Gly polymorphisms with Parkinson’s disease and response to dopamine agonists. J Neurol Sci. 2017;372:433–438. doi: 10.1016/j.jns.2016.08.005. [DOI] [PubMed] [Google Scholar]
  • 18.Zai CC, Manchia M, Sonderby IE, et al. Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders. World J Biol Psychiatry. 2015;16(3):171–179. doi: 10.3109/15622975.2014.953011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Crocq MA, Mant R, Asherson P, et al. Association between schizophrenia and homozygosity at the dopamine D3 receptor gene. J Med Genet. 1992;29(12):858–860. doi: 10.1136/jmg.29.12.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Nimgaonkar VL, Sanders AR, Ganguli R, et al. Association study of schizophrenia and the dopamine D3 receptor gene locus in two independent samples. Am J Med Genet. 1996;67(6):505–514. doi: 10.1002/(SICI)1096-8628(19961122)67:6<505::AID-AJMG1>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  • 21.Ma G, He Z, Fang W, et al. The Ser9Gly polymorphism of the dopamine D3 receptor gene and risk of schizophrenia: an association study and a large meta-analysis. Schizophr Res. 2008;101(1–3):26–35. doi: 10.1016/j.schres.2007.11.041. [DOI] [PubMed] [Google Scholar]
  • 22.Chen CH, Liu MY, Wei FC, Koong FJ, Hwu HG, Hsiao KJ. Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia. Am J Med Genet. 1997;74(1):40–43. doi: 10.1002/(sici)1096-8628(19970221)74:1<40::aid-ajmg9>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  • 23.Barlas IO, Cetin M, Erdal ME, et al. Lack of association between DRD3 gene polymorphism and response to clozapine in Turkish schizoprenia patients. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(1):56–60. doi: 10.1002/ajmg.b.30770. [DOI] [PubMed] [Google Scholar]
  • 24.Yao J, Pan YQ, Ding M, Pang H, Wang BJ. Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2015;168B(1):1–13. doi: 10.1002/ajmg.b.32281. [DOI] [PubMed] [Google Scholar]
  • 25.Yang B, Fan S, Zhi X, et al. Associations of MTHFR gene polymorphisms with hypertension and hypertension in pregnancy: a meta-analysis from 114 studies with 15411 cases and 21970 controls. PLoS One. 2014;9(2):e87497. doi: 10.1371/journal.pone.0087497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Utsunomiya K, Shinkai T, De Luca V, et al. Genetic association between the dopamine D3 gene polymorphism (Ser9Gly) and schizophrenia in Japanese populations: evidence from a case-control study and meta-analysis. Neurosci Lett. 2008;444(2):161–165. doi: 10.1016/j.neulet.2008.08.005. [DOI] [PubMed] [Google Scholar]
  • 27.Thakkinstian A, McEvoy M, Minelli C, et al. Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol. 2005;162(3):201–211. doi: 10.1093/aje/kwi184. [DOI] [PubMed] [Google Scholar]
  • 28.Munafò MR, Flint J. Meta-analysis of genetic association studies. Trends Genet. 2004;20(9):439–444. doi: 10.1016/j.tig.2004.06.014. [DOI] [PubMed] [Google Scholar]
  • 29.Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J. A method for meta-analysis of molecular association studies. Stat Med. 2005;24(9):1291–1306. doi: 10.1002/sim.2010. [DOI] [PubMed] [Google Scholar]
  • 30.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28(2):123–137. doi: 10.1002/gepi.20048. [DOI] [PubMed] [Google Scholar]
  • 32.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–1558. doi: 10.1002/sim.1186. [DOI] [PubMed] [Google Scholar]
  • 33.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Güzey C, Scordo MG, Spina E, Landsem VM, Spigset O. Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms. Eur J Clin Pharmacol. 2007;63(3):233–241. doi: 10.1007/s00228-006-0234-8. [DOI] [PubMed] [Google Scholar]
  • 35.Anney RJ, Rees MI, Bryan E, et al. Characterisation, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia. Mol Psychiatry. 2002;7(5):493–502. doi: 10.1038/sj.mp.4001003. [DOI] [PubMed] [Google Scholar]
  • 36.Baritaki S, Rizos E, Zafiropoulos A, et al. Association between schizophrenia and DRD3 or HTR2 receptor gene variants. Eur J Hum Genet. 2004;12(7):535–541. doi: 10.1038/sj.ejhg.5201180. [DOI] [PubMed] [Google Scholar]
  • 37.Cordeiro Q, Jr, Junqueira R, Vallada H. Estudo de associação entre o polimorfismo serina-9-glicina do receptor dopaminérgico D3 e esquizofrenia [Study of association between the ser-9-gly polymorphism of the D3 dopaminergic receptor and schizophrenia] Arq Neuropsiquiatr. 2001;59(2-A):219–222. Portuguese [with English abstract] [PubMed] [Google Scholar]
  • 38.Durany N, Thome J, Palomo A, Foley P, Riederer P, Cruz-Sanchez FF. Homozygosity at the dopamine D3 receptor gene in schizophrenic patients. Neurosci Lett. 1996;220(3):151–154. doi: 10.1016/s0304-3940(96)13251-1. [DOI] [PubMed] [Google Scholar]
  • 39.Ebstein RP, Macciardi F, Heresco-Levi U, et al. Evidence for an association between the dopamine D3 receptor gene DRD3 and schizophrenia. Hum Hered. 1997;47(1):6–16. doi: 10.1159/000154382. [DOI] [PubMed] [Google Scholar]
  • 40.Fathalli F, Rouleau GA, Xiong L, et al. No association between the DRD3 Ser9Gly polymorphism and schizophrenia. Schizophr Res. 2008;98(1–3):98–104. doi: 10.1016/j.schres.2007.07.002. [DOI] [PubMed] [Google Scholar]
  • 41.Gaitonde EJ, Morris A, Sivagnanasundaram S, McKenna PJ, Hunt DM, Mollon JD. Assessment of association of D3 dopamine receptor MscI polymorphism with schizophrenia: analysis of symptom ratings, family history, age at onset, and movement disorders. Am J Med Genet. 1996;67(5):455–458. doi: 10.1002/(SICI)1096-8628(19960920)67:5<455::AID-AJMG3>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  • 42.Hawi Z, McCabe U, Straub RE, et al. Examination of new and reported data of the DRD3/MscI polymorphism: no support for the proposed association with schizophrenia. Mol Psychiatry. 1998;3(2):150–155. doi: 10.1038/sj.mp.4000362. [DOI] [PubMed] [Google Scholar]
  • 43.Ishiguro H, Okuyama Y, Toru M, Arinami T. Mutation and association analysis of the 5′ region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia. Mol Psychiatry. 2000;5(4):433–438. doi: 10.1038/sj.mp.4000731. [DOI] [PubMed] [Google Scholar]
  • 44.Joober R, Toulouse A, Benkelfat C, et al. DRD3 and DAT1 genes in schizophrenia: an association study. J Psychiatr Res. 2000;34(4–5):285–291. doi: 10.1016/s0022-3956(00)00018-2. [DOI] [PubMed] [Google Scholar]
  • 45.Laurent C, Savoye C, Samolyk D, et al. Homozygosity at the dopamine D3 receptor locus is not associated with schizophrenia. J Med Genet. 1994;31(3):260. doi: 10.1136/jmg.31.3.260-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Lorenzo CV, Baca-Garcia E, Hernandez MD, et al. No association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and schizophrenia in a Spanish sample. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(3):344–346. doi: 10.1002/ajmg.b.30331. [DOI] [PubMed] [Google Scholar]
  • 47.Løvlie R, Thara R, Padmavathi R, Steen VM, McCreadie RG. Ser9Gly dopamine D3 receptor polymorphism and spontaneous dyskinesia in never-medicated schizophrenic patients. Mol Psychiatry. 2001;6(1):6–7. doi: 10.1038/sj.mp.4000822. [DOI] [PubMed] [Google Scholar]
  • 48.Maziade M, Martinez M, Rodrigue C, et al. Childhood/early adolescence-onset and adult-onset schizophrenia. Heterogeneity at the dopamine D3 receptor gene. Br J Psychiatry. 1997;170:27–30. doi: 10.1192/bjp.170.1.27. [DOI] [PubMed] [Google Scholar]
  • 49.Meszaros K, Lenzinger E, Hornik K, et al. Association study of schizophrenia spectrum disorders and dopamine D3 receptor gene: is schizoaffective disorder special? Psychiatry Res. 2000;96(2):179–183. doi: 10.1016/s0165-1781(00)00209-2. [DOI] [PubMed] [Google Scholar]
  • 50.Ohara K, Nakamura Y, Xie DW, et al. Polymorphisms of dopamine D2-like (D2, D3, and D4) receptors in schizophrenia. Biol Psychiatry. 1996;40(12):1209–1217. doi: 10.1016/0006-3223(95)00673-7. [DOI] [PubMed] [Google Scholar]
  • 51.Rietschel M, Nothen MM, Albus M, et al. Dopamine D3 receptor Gly9/Ser9 polymorphism and schizophrenia: no increased frequency of homozygosity in German familial cases. Schizophr Res. 1996;20(1–2):181–186. doi: 10.1016/0920-9964(95)00074-7. [DOI] [PubMed] [Google Scholar]
  • 52.Rybakowski JK, Borkowska A, Czerski PM, Hauser J. Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects. Mol Psychiatry. 2001;6(6):718–724. doi: 10.1038/sj.mp.4000927. [DOI] [PubMed] [Google Scholar]
  • 53.Saha N, Tsoi WF, Low PS, Basair J, Tay JS. Lack of association of the dopamine D3 receptor gene polymorphism (BalI) in Chinese schizophrenic males. Psychiatr Genet. 1994;4(4):201–204. doi: 10.1097/00041444-199400440-00002. [DOI] [PubMed] [Google Scholar]
  • 54.Shaikh S, Collier DA, Sham PC, et al. Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet. 1996;97(6):714–719. doi: 10.1007/BF02346178. [DOI] [PubMed] [Google Scholar]
  • 55.Sivagnanasundaram S, Morris AG, Gaitonde EJ, McKenna PJ, Mollon JD, Hunt DM. A cluster of single nucleotide polymorphisms in the 5′-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. Neurosci Lett. 2000;279(1):13–16. doi: 10.1016/s0304-3940(99)00921-0. [DOI] [PubMed] [Google Scholar]
  • 56.Spurlock G, Williams J, McGuffin P, et al. European multicentre association study of schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms. Am J Med Genet. 1998;81(1):24–28. doi: 10.1002/(sici)1096-8628(19980207)81:1<24::aid-ajmg5>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  • 57.Staddon S, Arranz MJ, Mancama D, et al. Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population. Schizophr Res. 2005;73(1):49–54. doi: 10.1016/j.schres.2004.06.011. [DOI] [PubMed] [Google Scholar]
  • 58.Talkowski ME, Mansour H, Chowdari KV, et al. Novel, replicated associations between dopamine D3 receptor gene polymorphisms and schizophrenia in two independent samples. Biol Psychiatry. 2006;60(6):570–577. doi: 10.1016/j.biopsych.2006.04.012. [DOI] [PubMed] [Google Scholar]
  • 59.Tanaka T, Igarashi S, Onodera O, et al. Association study between schizophrenia and dopamine D3 receptor gene polymorphism. Am J Med Genet. 1996;67(4):366–368. doi: 10.1002/(SICI)1096-8628(19960726)67:4<366::AID-AJMG9>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  • 60.Ventriglia M, Bocchio Chiavetto L, Bonvicini C, et al. Allelic variation in the human prodynorphin gene promoter and schizophrenia. Neuropsychobiology. 2002;46(1):17–21. doi: 10.1159/000063571. [DOI] [PubMed] [Google Scholar]
  • 61.Yang L, Li T, Wiese C, et al. No association between schizophrenia and homozygosity at the D3 dopamine receptor gene. Am J Med Genet. 1993;48(2):83–86. doi: 10.1002/ajmg.1320480205. [DOI] [PubMed] [Google Scholar]
  • 62.Morimoto K, Miyatake R, Nakamura M, Watanabe T, Hirao T, Suwaki H. Delusional disorder: molecular genetic evidence for dopamine psychosis. Neuropsychopharmacology. 2002;26(6):794–801. doi: 10.1016/S0893-133X(01)00421-3. [DOI] [PubMed] [Google Scholar]
  • 63.Jönsson EG, Kaiser R, Brockmöller J, Nimgaonkar VL, Crocq MA. Meta-analysis of the dopamine D3 receptor gene (DRD3) Ser9Gly variant and schizophrenia. Psychiatr Genet. 2004;14(1):9–12. doi: 10.1097/00041444-200403000-00002. [DOI] [PubMed] [Google Scholar]
  • 64.Nanko S, Sasaki T, Fukuda R, et al. A study of the association between schizophrenia and the dopamine D3 receptor gene. Hum Genet. 1993;92(4):336–338. doi: 10.1007/BF01247330. [DOI] [PubMed] [Google Scholar]
  • 65.Mant R, Williams J, Asherson P, Parfitt E, McGuffin P, Owen MJ. Relationship between homozygosity at the dopamine D3 receptor gene and schizophrenia. Am J Med Genet. 1994;54(1):21–26. doi: 10.1002/ajmg.1320540106. [DOI] [PubMed] [Google Scholar]
  • 66.Kennedy JL, Billett EA, Macciardi FM, et al. Association study of dopamine D3 receptor gene and schizophrenia. Am J Med Genet. 1995;60(6):558–562. doi: 10.1002/ajmg.1320600615. [DOI] [PubMed] [Google Scholar]
  • 67.Jönsson E, Lannfelt L, Sokoloff P, Schwartz JC, Sedvall G. Lack of association between schizophrenia and alleles in the dopamine D3 receptor gene. Acta Psychiatr Scand. 1993;87(5):345–349. doi: 10.1111/j.1600-0447.1993.tb03384.x. [DOI] [PubMed] [Google Scholar]
  • 68.Chang HA, Lu RB, Lin WW, et al. Lack of association between dopamine D3 receptor Ser9Gly polymorphism and schizophrenia in Han Chinese population. Acta Neuropsychiatr. 2007;19(6):344–350. doi: 10.1111/j.1601-5215.2007.00214.x. [DOI] [PubMed] [Google Scholar]
  • 69.Zai CC, Manchia M, De Luca V, et al. Association study of BDNF and DRD3 genes in schizophrenia diagnosis using matched case-control and family based study designs. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(8):1412–1418. doi: 10.1016/j.pnpbp.2010.07.019. [DOI] [PubMed] [Google Scholar]
  • 70.Zhang F, Fan H, Xu Y, et al. Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(5):613–619. doi: 10.1002/ajmg.b.31203. [DOI] [PubMed] [Google Scholar]
  • 71.Jönsson EG, Flyckt L, Burgert E, et al. Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis. Psychiatr Genet. 2003;13(1):1–12. doi: 10.1097/00041444-200303000-00001. [DOI] [PubMed] [Google Scholar]
  • 72.Nöthen MM, Cichon S, Propping P, Fimmers R, Schwab SG, Wildenauer DB. Excess of homozygosity at the dopamine D3 receptor gene in schizophrenia not confirmed. J Med Genet. 1993;30(8):708. doi: 10.1136/jmg.30.8.708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Nöthen MM, Körner J, Lannfelt L, et al. Lack of association between schizophrenia and alleles of the dopamine D1, D2, D3 and D4 receptor loci. Psychiatr Genet. 1993;3:89–94. [Google Scholar]
  • 74.Tee S, Tang P, Loh H. Genetic association analysis of dopamine DRD3 Ser9Gly polymorphism and schizophrenia in Malay population. Iran J Public Health. 2011;40(2):6–10. [PMC free article] [PubMed] [Google Scholar]
  • 75.Sáiz PA, Garcia-Portilla MP, Arango C, et al. Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: data from an association study. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(1):26–31. doi: 10.1016/j.pnpbp.2009.09.008. [DOI] [PubMed] [Google Scholar]
  • 76.Iwata Y, Matsumoto H, Minabe Y, et al. Early-onset schizophrenia and dopamine-related gene polymorphism. Am J Med Genet B Neuropsy-chiatr Genet. 2003;116B(1):23–26. doi: 10.1002/ajmg.b.10759. [DOI] [PubMed] [Google Scholar]
  • 77.Hauser J, Czerski PM, Czarny-Ratajczak M, et al. Brak asocjacji pomiędzy polimorfizmem genów DRD2 i DRD3 a schizofrenią [Lack of association between polymorphisms of DRD2 and DRD3 genes and schizophrenia] Post Psychiatr Neurol. 2000;9(2):149–157. Polish [with English abstract] [Google Scholar]
  • 78.Krelling R, Cordeiro Q, Miracca E, et al. Molecular genetic case-control women investigation from the first Brazilian high-risk study on functional psychosis. Rev Bras Psiquiatr. 2008;30(4):341–345. doi: 10.1590/s1516-44462008005000013. [DOI] [PubMed] [Google Scholar]
  • 79.Zheng C, Shen Y, Xu Q. Rs1076560, a functional variant of the dopamine D2 receptor gene, confers risk of schizophrenia in Han Chinese. Neurosci Lett. 2012;518(1):41–44. doi: 10.1016/j.neulet.2012.04.052. [DOI] [PubMed] [Google Scholar]
  • 80.Nunokawa A, Watanabe Y, Kaneko N, et al. The dopamine D3 receptor (DRD3) gene and risk of schizophrenia: case-control studies and an updated meta-analysis. Schizophr Res. 2010;116(1):61–67. doi: 10.1016/j.schres.2009.10.016. [DOI] [PubMed] [Google Scholar]
  • 81.Inada T, Sugita T, Dobashi I, et al. Dopamine D3 receptor gene polymorphism and the psychiatric symptoms seen in first-break schizophrenic patients. Psychiatr Genet. 1995;5(3):113–116. doi: 10.1097/00041444-199505030-00003. [DOI] [PubMed] [Google Scholar]
  • 82.A Z, Li H, Ma ZM, Zhang L. An association study of polymorphism of DRD3 gene with schizophrenia in Chinese Han population. J Dali Coll. 2004;3(1):3–4. Chinese. [Google Scholar]
  • 83.Zhao Z, Shi J, Dai J, et al. An association study between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Health Psychol J. 2002;10(3):163–165. Chinese. [Google Scholar]
  • 84.Tang YL, Wang YF, Cai ZJ, Zhou RL, Zhou CF. Association study of dopamine D3 receptor gene with schizophrenia subtypes. Chin J Psychiatry. 2002;35(1):11–14. Chinese [with English abstract] [Google Scholar]
  • 85.Yi Y, Wang JK, Wang MJ, Lin D, Qing HP. Association between Ser9-Gly polymorphism in dopamine D3 receptor gene and schizophrenia. J Clin Psychol Med. 2006;16(2):73–75. Chinese. [Google Scholar]
  • 86.Arj-Ong S, Thakkinstian A, McEvoy M, Attia J. A systematic review and meta-analysis of tumor necrosis factor α-308 polymorphism and Kawasaki disease. Pediatr Int. 2010;52(4):527–532. doi: 10.1111/j.1442-200X.2010.03105.x. [DOI] [PubMed] [Google Scholar]
  • 87.Dubertret C, Gorwood P, Ades J, Feingold J, Schwartz JC, Sokoloff P. Meta-analysis of DRD3 gene and schizophrenia: ethnic heterogeneity and significant association in Caucasians. Am J Med Genet. 1998;81(4):318–322. doi: 10.1002/(sici)1096-8628(19980710)81:4<318::aid-ajmg8>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  • 88.Walder DJ, Faraone SV, Glatt SJ, Tsuang MT, Seidman LJ. Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for Schizophrenia Study. Schizophr Res. 2014;157(1–3):142–148. doi: 10.1016/j.schres.2014.04.015. [DOI] [PubMed] [Google Scholar]
  • 89.Frey S. The economic burden of schizophrenia in Germany: a population-based retrospective cohort study using genetic matching. Eur Psychiatry. 2014;29(8):479–489. doi: 10.1016/j.eurpsy.2014.04.003. [DOI] [PubMed] [Google Scholar]
  • 90.Walton E, Liu J, Hass J, et al. MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls. Epigenetics. 2014;9(8):1101–1107. doi: 10.4161/epi.29223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Ruano-Ravina A, Pérez-Ríos M, Barros-Dios JM. Population-based versus hospital-based controls: are they comparable? Gac Sanit. 2008;22(6):609–613. doi: 10.1016/s0213-9111(08)75363-9. [DOI] [PubMed] [Google Scholar]
  • 92.Krebs MO, Sautel F, Bourdel MC, et al. Dopamine D3 receptor gene variants and substance abuse in schizophrenia. Mol Psychiatry. 1998;3(4):337–341. doi: 10.1038/sj.mp.4000411. [DOI] [PubMed] [Google Scholar]
  • 93.Yang H. The association between DRD3 Ser9Gly polymorphism and schizophrenia] [master’s thesis] Shenyang: China Medical University; 2005. Chinese. [Google Scholar]
  • 94.Liang KW. The association of DA2, DA3, and DA4 receptor gene polymorphology with schizophrenia also in medical jurisprudence and human genetics studies] [doctor’s thesis] Shenyang: China Medical University; 2005. Chinese. [Google Scholar]

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