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Neuropsychiatric Disease and Treatment logoLink to Neuropsychiatric Disease and Treatment
. 2018 Jan 3;14:153–164. doi: 10.2147/NDT.S156479

A meta-analysis of data associating DRD4 gene polymorphisms with schizophrenia

Feng-ling Xu 1, Xue Wu 1, Jing-jing Zhang 1, Bao-jie Wang 1, Jun Yao 1,✉
PMCID: PMC5757990  PMID: 29379288

Abstract

To explore the association between DRD4 polymorphisms and schizophrenia risk, a meta-analysis was carried out with 41 case–control articles. Specifically, we included 28 articles (5,735 cases and 5,278 controls) that pertained to the 48 bp variable number tandem repeat (VNTR) polymorphism, nine articles (1,517 cases and 1,746 controls) that corresponded to the 12 bp tandem repeat (TR), six articles (1,912 cases and 1,836 controls) that addressed the 120 bp TR, 10 articles (2,927 cases and 2,938 controls) that entailed the −521 C>T polymorphism, six articles (1,735 cases and 1,724 controls) that pertained to the −616 C>G polymorphism, and four articles (1,191 cases and 1,215 controls) that involved the −376 C>T polymorphism. Pooled analysis, subgroup analysis, and sensitivity analysis were performed, and the data were visualized by means of forest and funnel plots. Results of pooled analysis indicated that the −521 CC variant (Pz=0.009, odds ratio [OR] =1.218, 95% confidence interval [CI] =1.050–1.413) and genotype L/L (ie, long allele) of the 120 bp TR were risk factors of schizophrenia (Pz=0.004, OR =1.275, 95% CI =1.081–1.504). The 48 bp VNTR, the 12 bp TR, the −616 C>G polymorphism, and the −376 C>T polymorphism were not associated with schizophrenia. Additional research is warranted to explore the association between polymorphisms of DRD4 and schizophrenia risk.

Keywords: DRD4, schizophrenia, meta-analysis, polymorphism

Introduction

Schizophrenia is a chronic, severe mental disorder with a tremendously variable clinical presentation. Results of studies in which schizophrenia occurrence was evaluated among twins or children who were adopted have shown that this disease results from an interaction of genetics and environmental factors.1 Specifically, schizophrenia is a multigene disease with a heritability of 60%–70%.2 Although the pathogenesis and etiology of schizophrenia are not understood fully,3 a large body of evidence has indicated that dopamine dysfunction is involved in the occurrence of this disease.4–6

Dopamine is an endogenous neurotransmitter that primarily functions by binding to dopamine receptors, which have five types. The D4 receptor has attracted attention in the field of schizophrenia research. In postmortem brain striatum of patients with schizophrenia, the density of D4 receptor was significantly higher than in brain tissues of unaffected patients; in contrast, the density of D2 and D3 receptors remained modest.7 This upregulation of D4 receptor has been shown to be related to the disease rather than to pharmacological effects of treatment.8 The pharmacological characteristics of D4 resemble those of D2 and D3, but the affinity of D4 for clozapine is an order of magnitude higher.9 Hence, DRD4 (chromosome 11p15.5) is a potential susceptibility gene for schizophrenia.10

The SZGene database is a viable resource for ascertaining the risk of schizophrenia.11,12 Other investigators have determined that the −521 C>T and 120 bp tandem repeat (TR) polymorphisms in DRD4 are associated with nominally significant summary odds ratios (ORs) as risk factors for schizophrenia (P=0.003 and 0.005, respectively).11 However, despite a great deal of research, an association between DRD4 polymorphisms and schizophrenia risk remains debatable.

TRs in DRD4 include a 48 bp variable number TR (VNTR), a 12 bp TR, and a 120 bp TR. The 48 bp VNTR is located in the third exon of DRD4 and encodes a sequence of 16 amino acids in the region of the third cytoplasmic loop. Polymorphisms in the 48 bp VNTR were found to differ in the recruitment of cellular cAMP.13 The 12 bp TR (rs4646983) is located in the first exon of DRD4, which corresponds to the N terminus of the gene product. Variants of the 12 bp TR modify an N-terminal glycosylation site, which affects expression levels of the membrane protein.14 The 120 bp TR is located 1.2 kb upstream from the initiation codon, and polymorphisms at this site affect transcriptional efficiency.15 Some researchers noted that the 120 bp TR was associated with attention-deficit hyperactivity disorder (ADHD)16,17 and schizophrenia.18 However, Tsutsumi et al19 demonstrated that the 120 bp TR was not related to the risk of schizophrenia.

The −521 C>T polymorphism (rs1800955), located in the promoter region of DRD4, has been shown to be associated with novelty seeking20,21 and schizophrenia.22 Mitsuyasu et al suggested that the −521C variant could be a risk factor for schizophrenia among female patients.23 However, other investigators found no relationship between −521 C>T and schizophrenia.24 The −616 C>G (rs747302) and the −376 C>T (rs916455) polymorphisms are located in the promoter region of DRD4; these variants have not been associated conclusively with schizophrenia risk. A pooled analysis of data regarding polymorphisms in DRD4 and schizophrenia risk is warranted.

Meta-analyses are proven tools for ascertaining associations of gene polymorphisms with disease.25–27 Several meta-analyses previously have addressed the potential associations between DRD4 polymorphisms and schizophrenia risk.28–31 However, the authors of these studies examined just one polymorphic locus28 or did not include the latest data.31 Herein, we describe the results of our meta-analysis of the association between DRD4 and schizophrenia risk.

Materials and methods

Literature searches

The SZGene, PubMed, and China National Knowledge Infrastructure (CNKI) databases were searched with the keywords “schizophrenia” and “DRD4”. Reference lists from relevant articles also were screened to identify additional studies.

Inclusion criteria and exclusion criteria

Studies with the following features were included in the meta-analysis: 1) case–control design; 2) involved patients with schizophrenia; 3) presented relevant data for case and control groups (eg, allele/genotype frequencies, sample size, ethnicity, schizophrenia diagnostic criteria, and control group source); 4) removed duplicate sample data; and 5) published before September 1, 2017. Studies were excluded for the following reasons: 1) no control group; 2) no usable genotype frequency data (attempts were made to contact authors via email for these data); and 3) duplicate reported sample data.

Statistical analysis

A meta-analysis was carried out using Stata Version 10.0 (StataCorp LP, College Station, TX, USA). The P-value of Hardy–Weinberg equilibrium (PHWE) was calculated for the control groups. ORs and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Under a random model,32,33 associations between DRD4 and the risk of schizophrenia were analyzed. A random model took into account population differences and heterogeneity among studies.25,34 Pairwise differences between genotypes (AA vs aa, Aa vs aa, and AA vs Aa [A being the risk factor]) were used to determine a suitable genetic model.35

The heterogeneity of the studies was determined by Cochran’s chi-square-based Q-statistic test.36 The degree of heterogeneity was expressed as I2 and was divided into low (I2<25%), medium (I2~50%), and high (I2>75%) heterogeneity groups.37 I2>50% was regarded as indicating substantial heterogeneity.38 Publication bias was calculated using Egger’s test and was represented as a funnel plot in which the standard error of log(OR) of each study was plotted against its log(OR). A sensitivity analysis was conducted to test the impact of removing each single study on the pooled result. Statistical power was calculated by means of the PS program, as described previously.39,40 P-values corresponding to association, heterogeneity, and publication bias tests were represented as Pz, Ph, and Pe, respectively. Statistical significance was defined as P<0.05 for all analyses.41

Results

Description of studies

A total of 211 English-language articles were obtained from SZGene and PubMed, and 14 Chinese-language articles were obtained from CNKI. After removing duplicate studies and those that did not meet our inclusion criteria, 41 articles were used in the meta-analysis (Figure 1). Specifically, 28 articles addressed the 48 bp VNTR,23,42–68 nine articles involved the 12 bp TR,23,43,48–50,69–72 six articles pertained to the 120 bp TR,18,19,65,72–74 10 articles addressed the −521 C>T polymorphism,18,22–24,58,72–76 six articles referred to −616 C>G,18,23,72,74–76 and four articles entailed −376 C>T.18,23,72,75 Details of these studies are listed in Table 1. We omitted loci from our meta-analysis that were not represented in at least four articles.

Figure 1.

Figure 1

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Study selection process in this meta-analysis.

Abbreviations: CNKI, China National Knowledge Infrastructure; VNTR, variable number tandem repeat.

Table 1.

Characteristics of studies that qualified to be included in the meta-analysis

Author Year Country Ethnicity Controls source Mean age of control group Gender index (case) Gender index (control)
Kaiser et al42 2000 German Caucasian Hospital based 43.53 0.83 0.34
Kohn et al43,a 1997 Israel Israeli Hospital based – – –
Kohn et al43,b 1997 Israel Israeli Hospital based – – –
Serretti et al44,69 1999, 2001 Italy Caucasian Hospital based 47.45 – 1.27
Hattori et al45 2009 Japan East Asian Population based 46.70 1.00 1.00
Tanaka et al46 1995 Japan East Asian Population based 45.80 0.84 0.56
Nanko et al47 1993 Japan East Asian Population based – – –
Petronis et al48 1995 USA, Canada Caucasian Hospital based – – –
Ohara et al49 1996 Japan East Asian Population based 34.40 0.99 1.37
Aguirre et al50 2007 Mexico Indian Population based 40.00 0.97
Mitsuyasu et al23,c 2007 Japan East Asian Hospital based 50.20 0.81 0.76
Daniels et al51 1994 UK Caucasian Hospital based 49.60 0.80 0.68
Sommer et al52 1993 Minnesota Caucasian Population based 65.00 0.44 1.61
Rao et al53 1994 USA Caucasian Population based – – –
Hong et al54 1997 Taiwan East Asian Hospital based 28.70 0.68 0.62
Jonsson et al55 1996 Sweden Caucasian Population based 38.70 0.573 0.73
Rinetti et al56 2001 Mexico Mestizos Hospital based – – –
Fujiwara et al57 1997 Japan East Asian Population based – – –
Lung et al58 2006 Taiwan East Asian Population based 45.37 – –
Nakamura et al59 1995 Japan East Asian Population based – – –
Lung et al60 2009 Taiwan East Asian Population based – – –
Fresan et al61 2007 Mexico Caucasian Population based 34.60 0.45 94.23
Zhang et al62 2003 China East Asian Population based 42.00 0.43 –
Tang et al68 2001 China East Asian Population based 33.00 0.44 0.40
Liang67 2005 China East Asian Population based 26.00 0.98 0.98
Zhao et al63 2005 China East Asian Population based 34.00 0.88 0.88
Zhao et al64 2006 China East Asian Population based 29.40 0.84 1.00
Chen et al65 2016 China East Asian Hospital based 39.19 0.81 0.89
Lu et al66 2003 China East Asian Population based 65.00 0.74 1.22
Serretti et al69 1999 Italy Caucasian Population based – – –
Hong et al70 1998 Taiwan East Asian Hospital based 30.20 28.70 0.62
Catalano et al71 1993 Italy Caucasian Hospital based 46.90 30.00 1.34
Nakajima et al72 2007 Japan East Asian Population based 47.00 46.70 1.00
Okuyama et al22 1999 Japan East Asian Population based 47.10 47.90 0.63
Mitsuyasu et al75,d 2001 Japan East Asian Hospital based 51.50 50.50 0.75
Jonsson et al24 2001 Sweden Caucasian Population based 44.80 42.60 0.80
Pai et al73 2015 India Indian Population based – – –
Xing et al18 2003 China East Asian Hospital based 41.20 41.80 –
Lai et al74 2010 China East Asian Hospital based 40.60 43.20 1.00
Zhong et al76 2010 China East Asian Population based 39.20 37.50 1.00
Tsutsumi et al19 2011 Japan East Asian Hospital based 47.20 42.10 0.50
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Notes: Gender index = female/male.

a

Ethnicity is Ashkenazi which included Jews whose origin (or whose parents’ origin), was in European countries, apart from the Balkans;

b

ethnicity is non-Ashkenazi which included Jews whose origin was in North Africa or Asia.

c

Included 48 bp VNTR, 12 bp TR, and 120 bp TR;

d

did not include 48 bp VNTR, 12 bp TR, and 120 bp TR.

Results of data analysis

No association between the 48 bp VNTR and schizophrenia risk

Allele frequencies of the 48 bp VNTR are listed in Table 2. Results of pooled analyses are summarized in Table 3, and data from subgroup analyses are depicted in Table 4. We were unable to obtain specific data regarding the number of 7-repeat (7R) alleles in the 48 bp VNTR,44 despite multiple attempts to contact the corresponding author. Thus, this study was omitted from our analysis of an association between 7R and schizophrenia risk. When we conducted a pooled analysis of the remaining 5,316 cases and 4,677 controls, we found that 7R was not associated with schizophrenia risk (Pz=0.349, OR =1.071, 95% CI =0.928–1.236) under a random effects model with a power of 0.271 (Table 3 and Figure S1).35 No association was found in subgroup analysis by ethnicity (ie, Caucasian [Pz=0.238, OR =1.127, 95% CI =0.924–1.375], East Asian [Pz=0.901, OR =0.966, 95% CI =0.560–1.667], Indian [Pz=0.211, OR =0.772, 95% CI =0.514–1.158], Mestizos [Pz=0.310, OR =1.413, 95% CI =0.725–2.754], and Israeli [Pz=0.512, OR =1.164, 95% CI =0.739–1.835]). Moreover, no association of 7R with the risk of schizophrenia was ascertained in subgroup analysis by source of controls. No significant heterogeneity was found in the pooled or subgroup analyses.

Table 2.

Allele frequency of 48 bp VNTR polymorphism

Author Allele distribution
Allele frequency
Cases (n)
Controls (n)
Cases (n)
Controls (n)
Short (≤4) Long (≥5) Short (≤4) Long (≥5) 7R Others 7R Others
Kaiser et al42 1,006 270 1,182 322 232 1,044 282 1,222
Kohn et al43,a – – – – 22 76 52 238
Kohn et al43,b – – – – 13 85 17 101
Serretti et al44,69 709 129 990 212 – – – –
Hattori et al45 1,066 54 1,076 60 2 1,118 6 1,130
Tanaka et al46 134 6 133 7 0 140 2 138
Nanko et al47 148 12 152 10 2 158 0 162
Petronis et al48 77 23 154 46 21 79 32 168
Ohara et al49 286 20 227 15 18 288 10 232
Aguirre et al50 120 72 224 114 46 146 98 240
Mitsuyasu et al23,c 406 18 447 27 1 423 3 471
Daniels et al51 159 53 193 45 52 160 45 193
Sommer et al52 182 48 171 59 43 187 54 176
Rao et al53 39 17 31 9 17 39 8 32
Hong et al54 172 6 78 6 0 178 0 84
Jonsson et al55 187 49 124 28 42 194 23 129
Rinetti et al56 36 38 48 26 31 43 25 49
Fujiwara et al57 34 0 22 0 0 34 0 22
Lung et al58 1,216 44 846 10 3 1,257 0 856
Nakamura et al59 189 13 98 6 0 202 0 104
Lung et al60 1,774 54 838 8 0 1,828 0 846
Fresan et al61 88 54 285 119 47 95 104 300
Zhang et al62 131 3 145 7 0 134 0 152
Tang et al68 980 40 332 10 1 1,019 0 342
Liang67 176 26 185 25 4 198 2 208
Zhao et al63 78 246 75 249 3 321 6 318
Zhao et al64 41 121 40 136 0 162 3 173
Chen et al65 219 49 299 37 0 268 0 336
Lu et al66 155 5 157 3 1 159 0 160
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Notes:

a

Ethnicity is Ashkenazi which included Jews whose origin (or whose parents’ origin), was in European countries, apart from the Balkans;

b

ethnicity is non-Ashkenazi which included Jews whose origin was in North Africa or Asia.

c

Included 48 bp VNTR, 12 bp TR, and 120 bp TR.

Abbreviations: 7R, 7 repeat; VNTR, variable number tandem repeat.

Table 3.

Pooled associations of DRD4 polymorphisms and schizophrenia

Loci Genetic model Studies
(n)		 Statistical model OR 95% CI Pz I2 Ph Pe
48 bp VNTR Allele contrast (7R and others) 27 Random 1.071 0.928–1.236 0.349 8.1 0.352 0.727
Allele contrast (S and L) 27 Random 1.135 0.988–1.303 0.073 44.0 0.009 0.151
12 bp TR Allele contrast 9 Random 1.037 0.885–1.215 0.659 0.0 0.931 0.584
Homozygous codominant 9 Random 0.756 0.434–1.317 0.323 0.0 0.729 0.214
Heterozygous codominant 9 Random 1.117 0.930–1.341 0.236 0.0 0.644 0.077
Dominant 9 Random 1.083 0.907–1.293 0.377 0.0 0.834 0.192
Recessive 9 Random 0.724 0.417–1.259 0.253 0.0 0.681 0.180
120 bp TR Allele contrast 6 Random 1.189 1.040–1.358 0.011 37.1 0.159 0.701
Homozygous codominant 6 Random 1.291 0.892–1.868 0.176 47.2 0.092 0.213
Heterozygous codominant 6 Random 1.010 0.744–1.372 0.949 22.9 0.262 0.223
Dominant 6 Random 1.152 0.837–1.584 0.386 34.3 0.179 0.176
Recessive 6 Random 1.275 1.081–1.504 0.004 33.1 0.187 0.756
−521 T>C Allele contrast 10 Random 1.113 1.024–1.209 0.011 16.2 0.294 0.628
Homozygous codominant 10 Random 1.240 1.041–1.477 0.016 18.7 0.271 0.765
Heterozygous codominant 10 Random 1.105 0.971–1.256 0.129 13.8 0.316 0.751
Dominant 10 Random 1.136 1.004–1.289 0.043 19.2 0.266 0.620
Recessive 10 Random 1.177 1.024–1.353 0.021 0.0 0.467 0.812
−616 G>C Allele contrast 6 Random 1.103 0.991–1.226 0.071 6.7 0.373 0.604
Homozygous codominant 6 Random 0.637 0.469–0.866 0.004 46.4 0.096 0.488
Heterozygous codominant 6 Random 1.123 0.974–1.296 0.110 0.0 0.986 0.169
Dominant 6 Random 1.133 0.991–1.295 0.068 0.0 0.889 0.965
Recessive 6 Random 1.140 0.840–1.548 0.400 48.3 0.085 0.338
−376 C>T Allele contrast 4 Random 1.124 0.940–1.344 0.198 0.0 0.707 0.200
Homozygous codominant 4 Random 0.854 0.416–1.749 0.665 0.0 0.996 0.456
Heterozygous codominant 4 Random 0.730 0.351–1.520 0.401 0.0 0.993 0.911
Dominant 4 Random 0.820 0.401–1.676 0.586 0.0 0.994 0.583
Recessive 4 Random 1.171 0.962–1.425 0.117 0.0 0.707 0.214
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Notes: L, long allele; S, short allele.

Abbreviations: CI, confidence interval; OR, odds ratio; 7R, 7 repeat; TR, tandem repeat; VNTR, variable number TR.

Table 4.

Subgroup associations of DRD4 polymorphisms with schizophrenia

Polymorphism Subgroup analysis Studies (n) OR 95% CI Pz Ph I2
48 bp VNTR (7R and others) Overall 22 1.095 0.953–1.259 0.349 0.352 8.1
Ethnicity
Caucasian 7 1.127 0.924–1.375 0.238 0.195 30.6
East Asian 11 0.966 0.560–1.667 0.901 0.413 3.1
Indian 1 0.772 0.514–1.158 0.211 – –
Mestizos 1 1.413 0.725–2.754 0.310 – –
Israeli 2 1.164 0.739–1.835 0.512 0.441 0.0
Source of controls
Population based 15 1.031 0.796–1.336 0.816 0.242 18.9
Hospital based 7 1.070 0.917–1.248 0.393 0.490 0.0
48 bp VNTR (S and L) Overall 26 1.147 1.003–1.312 0.073 0.009 44.0
Ethnicity
Caucasian 8 1.037 0.882–1.219 0.662 0.173 32.0
East Asian 16 1.165 0.919–1.475 0.206 0.014 49.1
Indian 1 1.179 0.815–1.705 0.382 – –
Mestizos 1 1.949 1.007–3.770 0.048 – –
Israeli
Source of controls
Population based 18 1.165 0.977–1.390 0.089 0.069 35.4
Hospital based 8 1.091 0.862–1.381 0.468 0.016 59.2
12 bp TR Overall 10 1.083 0.907–1.293 0.377 0.834 0.0
Ethnicity
Indian 1 0.927 0.533–1.612 0.788 – –
Caucasian 3 0.787 0.509–1.218 0.283 0.611 0.0
East Asian 4 1.178 0.949–1.462 0.137 0.910 0.0
Israeli 2 1.312 0.642–2.679 0.456 0.610 0.0
Source of controls
Population based 4 1.133 0.908–1.413 0.270 0.710 0.0
Hospital based 6 1.012 0.706–1.450 0.949 0.272 21.5
120 bp TR Overall 6 1.275 1.081–1.504 0.004 0.187 33.1
Ethnicity
East Asian 5 1.317 1.108–1.565 0.002 0.196 33.9
Indian 1 0.979 0.629–1.524 0.924 – –
Source of controls
Population based 2 1.102 0.892–1.360 0.368 0.551 0.0
Hospital based 4 1.319 1.134–1.708 0.002 0.225 31.2
−521 T>C Overall 10 1.177 1.024–1.353 0.021 0.467 0.0
Ethnicity
Caucasian 1 1.136 0.670–1.925 0.636 – –
East Asian 8 1.218 1.050–1.413 0.009 0.571 0.0
Indian 1 0.715 0.395–1.293 0.267
Source of controls
Population based 6 1.188 0.972–1.451 0.092 0.258 23.5
Hospital based 4 1.143 0.901–1.450 0.270 0.561 0.0
−616 G>C Overall 6 1.133 0.991–1.295 0.068 0.889 0.0
Source of controls
Population based 2 1.117 0.915–1.364 0.275 0.966 0.0
Hospital based 4 1.146 0.956–1.317 0.140 0.645 0.0
−376 C>T Overall 4 1.171 0.962–1.425 0.117 0.707 0.0
Source of controls
Population based 1 1.079 0.805–1.447 0.611 – –
Hospital based 3 1.252 0.960–1.632 0.117 0.653 0.0
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Notes: L, long allele; S, short allele.

Abbreviations: CI, confidence interval; OR, odds ratio; 7R, 7 repeat; TR, tandem repeat; VNTR, variable number TR.

To incorporate data from the study of Serretti et al,44 the 48 bp VNTR was classified into S (short allele, ≤4 TRs) and L (long allele, ≥5 TRs) groups. In the study by Kohn et al,43 the 48 bp VNTR data could not be categorized into S and L groups, so this study was omitted from the analysis. The remaining data comprised 5,637 cases and 5,074 controls (Table 3 and Figure S2). Results of a pooled analysis indicated no relationship between this polymorphism and schizophrenia risk (Pz=0.073, OR =1.135, 95% CI =0.988–1.303) with a power of 0.909. No association was found in the subgroup analysis by source of control or by ethnicity, except for Mestizos (Pz=0.048, OR =1.949, 95% CI =1.007–3.77). Significant heterogeneity was found in the pooled analysis (Pe=0.009, I2=44%) and in the subgroup analysis by ethnicity in the East Asian subgroup (Pe=0.014, I2=49.1%) and by source of control in the hospital-based subgroup (Pe=0.016, I2 =59.2%).

No association between the 12 bp TR and schizophrenia risk

To evaluate the relationship between the 12 bp TR and the risk of schizophrenia, 1,517 cases and 1,746 controls were included (Table 5 and Figures S3–S7). Allele groups were defined as in (ie, inserted) and de (ie, deleted). In the dominant model,34,35 the pooled OR using a random effects model was 1.083 (Pz=0.377, 95% CI =0.907–1.293) with a power of 0.154 (Table 3). No association was found in subgroup analysis by ethnicity or by source of controls (Table 4). No significant heterogeneity was observed in the pooled or subgroup analyses.

Table 5.

Genotype distribution and allele frequency of 12 bp TR

Author Genotype distribution
PHWE Allele frequency
Cases, n
Controls, n
Case (%)
Controls (%)
in/in in/de de/de in/in in/de de/de in de in de
Petronis et al48 43 6 1 80 20 0 0.267 92.00 8.00 90.00 10.00
Ohara et al49 144 9 0 116 5 0 0.816 97.06 2.94 97.93 2.07
Serretti et al44,69 184 28 0 225 37 1 0.689 0.93 0.07 0.93 0.07
Aguirre et al50 48 34 1 75 55 4 0.102 78.31 21.69 76.49 23.51
Mitsuyasu et al23,a 136 56 5 176 53 10 0.027 83.20 16.70 84.70 15.30
Kohn et al43,b 40 9 0 126 19 0 0.311 94.00 6.00 91.00 9.00
Kohn et al43,c 44 4 1 53 6 0 0.416 94.00 6.00 94.00 6.00
Hong et al54 68 10 2 35 7 0 0.556 91.25 8.75 91.70 8.30
Catalano et al71 76 3 0 69 6 0 0.718 98.10 1.90 96.00 4.00
Nakajima et al72 413 140 12 431 119 18 0.008 85.50 14.50 86.50 13.50
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Notes: PHWE, P-value of Hardy–Weinberg equilibrium.

a

Included 48 bp VNTR, 12 bp TR, and 120 bp TR.

b

Ethnicity is Ashkenazi which included Jews whose origin (or whose parents’ origin), was in European countries, apart from the Balkans;

c

ethnicity is non-Ashkenazi which included Jews whose origin was in North Africa or Asia.

Abbreviations: de, deleted; in, inserted; TR, tandem repeat.

Genotype L/L of the 120 bp TR might be a risk factor for schizophrenia

In a random model, a pooled analysis was conducted (1,912 cases and 1,836 controls) to evaluate the relationship between genotype L/L of the 120 bp TR and schizophrenia risk (Table 6 and Figures S8–S12). In the recessive model,34,35 genotype L/L was found to be a potential risk factor for schizophrenia (Pz=0.004, OR =1.275, 95% CI =1.081–1.504) with a power of 0.959 (Table 3). Findings from subgroup analysis indicated significant associations in East Asian (Pz=0.002, OR =1.317, 95% CI =1.108–1.565) and hospital-based subgroups (Pz=0.002, OR =1.319, 95% CI =1.134–1.708) (Table 4). No association was found for the other subgroups, and no significant heterogeneity was ascertained in the pooled or subgroup analyses.

Table 6.

Genotype distribution and allele frequency of 120 bp TR

Author Genotype distribution
PHWE Allele frequency
Cases, n
Controls, n
Cases (%)
Controls (%)
S/S S/L L/L S/S S/L L/L S L S L
Mitsuyasu et al23,a 10 75 129 13 87 139 0.898 77.80 22.20 76.40 23.60
Pai et al73 23 77 87 11 61 64 0.501 32.90 67.10 30.50 69.50
Xing et al18 20 77 113 28 98 80 0.816 27.90 72.10 37.40 62.60
Nakajima et al72 24 183 362 33 192 345 0.363 20.00 80.00 23.00 78.00
Tsutsumi et al19 24 138 248 16 158 211 0.041 22.68 77.32 24.68 75.32
Lai et al74 28 161 133 40 166 94 0.013 33.70 66.30 41.00 59.00
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Notes: L, long allele; PHWE, P-value of Hardy–Weinberg equilibrium; S, short allele.

a

Included 48 bp VNTR, 12 bp TR, and 120 bp TR.

Abbreviation: TR, tandem repeat.

The −521 CC variant might be a risk factor for schizophrenia

Pooled and subgroup analyses were performed in a random model with 2,927 cases and 2,938 controls (Table 7 and Figures S13–S17). In the recessive model, −521 CC was found to be a potential risk factor for schizophrenia in the pooled analysis (Pz=0.021, OR =1.177, 95% CI =1.024–1.353) with a power of 0.656 (Table 3). In subgroup analyses by ethnicity and source of controls, the association was only detected in the East Asian subgroup (Pz=0.009, OR =1.218, 95% CI =1.050–1.413) (Table 4). No significant heterogeneity was noted in the pooled or subgroup analyses.

Table 7.

Genotype distribution and allele frequency of −521 C>T

Author Genotype distribution
PHWE Allele frequency
Cases, n
Controls, n
Cases (%)
Controls (%)
CC CT TT CC CT TT C T C T
Okuyama et al22 58 125 69 38 142 89 0.119 48.00 52.00 41.00 59.00
Mitsuyasu et al23,a 33 106 67 31 115 93 0.623 41.75 58.25 37.05 62.95
Mitsuyasu et al75,b 25 122 61 25 110 75 0.109 41.30 58.70 38.10 61.90
Lung et al58 80 320 230 48 204 173 0.294 38.10 61.90 35.30 64.70
Jonsson et al24 23 74 35 60 205 118 0.061 45.50 54.50 42.00 58.00
Pai et al73 27 92 62 26 77 29 0.055 40.30 59.70 48.90 51.10
Xing et al18 37 103 70 25 111 70 0.059 42.10 57.90 39.10 60.90
Nakajima et al72 106 270 190 89 285 195 0.368 43.00 58.00 41.00 59.00
Lai et al74 87 115 120 81 95 124 – 44.88 55.12 42.83 57.17
Zhong et al76 62 78 60 53 64 83 – 45.91 54.09 42.50 57.50
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Notes: PHWE, P-value of Hardy–Weinberg equilibrium.

a

Included 48 bp VNTR, 12 bp TR, and 120 bp TR;

b

did not include 48 bp VNTR, 12 bp TR, and 120 bp TR.

Abbreviation: TR, tandem repeat.

No association between −616 C>G and the risk of schizophrenia

In a random model, pooled (Table 3) and subgroup (Table 4) analyses were performed with 1,735 cases and 1,724 controls (Table 8 and Figures S18–S22). Using the dominant model, results of the pooled analysis indicated a lack of an association between −616 C>G and schizophrenia risk (Pz=0.068, OR =1.133, 95% CI =0.991–1.295) with a power of 0.45. All cases and controls in this analysis corresponded to the East Asian subgroup. Findings from a subgroup analysis of source of controls showed no association. There was no significant heterogeneity in the pooled or subgroup analyses.

Table 8.

Genotype distribution and allele frequency of −616 C>G

Author Genotype distribution
PHWE Allele frequency
Cases, n
Controls, n
Cases (%)
Controls (%)
GG GC CC GG GC CC G C G C
Mitsuyasu et al23,a 102 89 19 112 98 30 0.243 69.80 30.20 67.10 32.90
Mitsuyasu et al75,b 89 89 30 100 85 25 0.296 64.20 35.80 67.90 32.10
Xing et al18 83 100 27 91 102 13 0.025 63.30 36.70 68.90 31.10
Nakajima et al72 267 248 49 285 224 59 0.134 69.00 31.00 69.50 29.50
Lai et al74 161 113 48 166 102 32 0.009 67.55 32.45 72.33 27.67
Zhong et al76 112 77 31 107 68 25 0.010 68.41 31.59 70.50 29.50
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Notes: PHWE, P-value of Hardy–Weinberg equilibrium.

a

Included 48 bp VNTR, 12 bp TR, and 120 bp TR;

b

did not include 48 bp VNTR, 12 bp TR, and 120 bp TR.

Abbreviation: TR, tandem repeat.

No association of the −376 C>T variant with schizophrenia

We assessed the relationship between the −376 C>T polymorphism and schizophrenia risk in pooled and subgroup analyses of 1,191 cases and 1,215 controls in a random model (Tables 3, 4, and 9 and Figures S23–S27). In the recessive model, −376 C>T was not associated with the risk of schizophrenia in a pooled analysis (Pz=0.117, OR =1.171, 95% CI =0.962–1.425) with a power of 0.357 (Table 3). No association was detected in subgroup analyses by ethnicity or source of controls (Table 4). No significant heterogeneity was ascertained in the pooled or subgroup analyses.

Table 9.

Genotype distribution and allele frequency of −376 C>T

Author Genotype distribution
PHWE Allele frequency
Cases, n
Controls, n
Cases (%)
Controls (%)
CC CT TT CC CT TT C T C T
Mitsuyasu et al23,a 177 34 1 193 43 1 0.39 91.50 8.50 90.45 9.45
Mitsuyasu et al75,b 179 28 1 168 41 1 0.367 92.80 0.72 89.80 1.02
Xing et al74 137 66 7 127 74 5 0.126 81.00 19.00 79.60 20.40
Nakajima et al72 453 100 8 447 108 7 0.869 90.00 10.00 89.50 10.50
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Notes: PHWE, P-value of Hardy–Weinberg equilibrium.

a

Included 48 bp VNTR, 12 bp TR, and 120 bp TR;

b

did not include 48 bp VNTR, 12 bp TR, and 120 bp TR.

Abbreviation: TR, tandem repeat.

Sensitivity analysis

The results of sensitivity analyses showed that the combined ORs did not change significantly for meta-analyses in which each study was omitted singly. Thus, the results were considered stable and reasonable.

Publication bias

Potential publication bias was found in funnel plots in which the standard error of log(OR) of each study was plotted against its log(OR). No evidence of publication bias was found in pooled analyses (Figures 2–8).

Figure 2.

Figure 2

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Funnel plot analysis for the detection of publication bias in the association between the 48 bp VNTR (7R vs others) and schizophrenia.

Abbreviations: OR, odds ratio; 7R, 7 repeat; VNTR, variable number tandem repeat.

Figure 3.

Figure 3

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Funnel plot analysis for the detection of publication bias in the association between 48 bp VNTR (L vs S) and schizophrenia.

Notes: L, long allele; S, short allele.

Abbreviations: OR, odds ratio; VNTR, variable number tandem repeat.

Figure 4.

Figure 4

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Funnel plot analysis for the detection of publication bias in the association between 12 bp TR and schizophrenia.

Abbreviations: OR, odds ratio; TR, tandem repeat.

Figure 5.

Figure 5

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Funnel plot analysis for the detection of publication bias in the association between 120 bp TR and schizophrenia.

Abbreviations: OR, odds ratio; TR, tandem repeat.

Figure 6.

Figure 6

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Funnel plot analysis for the detection of publication bias in the association between −521 C>T and schizophrenia.

Abbreviation: OR, odds ratio.

Figure 7.

Figure 7

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Funnel plot analysis for the detection of publication bias in the association between −616 C>G and schizophrenia.

Abbreviation: OR, odds ratio.

Figure 8.

Figure 8

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Funnel plot analysis for the detection of publication bias in the association between −376 C>T and schizophrenia.

Abbreviation: OR, odds ratio.

Discussion

Results of other studies have associated the 7R polymorphism with ADHD in a meta-analysis77 and with increased brain activity to unpleasant stimuli.78 We sought to determine whether 7R was also associated with schizophrenia risk. Findings of our pooled and subgroup analyses indicated that 7R was not associated with the risk of schizophrenia. Similarly, we found that the 48 bp VNTR (classified into L and S groups) was not associated with schizophrenia risk in most of our pooled and subgroup analyses, which is consistent with previously published meta-analyses.29,30 Only in the Mestizos subgroup, an association was detected. Our literature search yielded one article addressing Mestizos patients, and this article had an insufficient sample size to verify this association. Hence, the utility of the 48 bp VNTR as a means to assess schizophrenia risk in the Mestizo population warrants additional investigation. Lung et al28 demonstrated an association between the 48-bp VNTR and schizophrenia risk but noted that sample bias might have led to a false-positive result.29

We determined that the L/L genotype of the 120 bp TR and the −521 CC variant might be risk factors for schizophrenia among East Asians; this relationship was not found in other populations. This discrepancy between East Asians and other populations might have resulted from the small sample sizes of the other ethnicity subgroups, the distinct genetic backgrounds, or different demographic or lifestyle factors within the subgroups. The statistical power for the pooled analysis of the 12 bp TR, the −616 C>G polymorphism, and the −376 C>T variant was low. Therefore, these results will need to be validated further. In a study of linkage disequilibrium (LD) of DRD4 that included 17 polymorphisms,23 the authors found no LD between −521 T>C and 120 bp TR (r2=0.00). For all pairs of −616 C>G, −376 C>T, 12 bp TR, and 48 bp VNTR, no significant LD was observed.

Multiple meta-analyses have been conducted to date on the association between DRD4 and schizophrenia. The current meta-analysis included some new studies, involved a large sample size, and had high statistical power. We addressed six loci in DRD4; no other meta-analysis involving four of these loci (12 bp TR, 120 bp TR, −616 C>G, and −376 C>T) has been carried out. Moreover, we conducted subgroup analysis by ethnicity and by source of controls and included data both from SZGene and the CNKI databases.

The results described herein should be interpreted with caution. The present study was limited by a lack of exact allele/genotype frequencies for some of the included articles, despite our efforts to acquire this information from the corresponding authors. Therefore, these articles were omitted from the meta-analysis. Second, controls in some of the articles did not conform to Hardy–Weinberg equilibrium because of sample bias. Third, case–control studies were included in this meta-analysis, but family-based studies were not.77 The ability to exploit cosegregation of variants with disease within families helps distinguish causal from noncausal factors. Family-based studies are more powerful to detect risk factors of diseases.79 Moreover, we did not address possible interactions between the six loci and epigenetic factors. An association between DRD4 and schizophrenia risk was detected based on case–control studies rather than on functional ones. Our results will need to be validated on a functional level.

Conclusion

The −521 CC variant and the L/L genotype of the 120-bp TR might be risk factors for schizophrenia. No association with schizophrenia was detected for the 48 bp VNTR, the 12 bp TR, −616 C>G, or −376 C>T. Our results may provide an informative reference for subsequent genome-wide association studies.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No 81601653) and the Doctoral Research Start Foundation of Liaoning Province (201601115) (both to Dr Jun Yao). The article was edited by native English-speaking experts of BioMed Proofreading, LLC.

Footnotes

Disclosure

The authors report no conflicts of interest in this work.

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