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

Figures & data

Figure 1 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 al^Citation42	2000	German	Caucasian	Hospital based	43.53	0.83	0.34
Kohn et al^Citation43,a	1997	Israel	Israeli	Hospital based	–	–	–
Kohn et al^Citation43,b	1997	Israel	Israeli	Hospital based	–	–	–
Serretti et al^Citation44,Citation69	1999, 2001	Italy	Caucasian	Hospital based	47.45	–	1.27
Hattori et al^Citation45	2009	Japan	East Asian	Population based	46.70	1.00	1.00
Tanaka et al^Citation46	1995	Japan	East Asian	Population based	45.80	0.84	0.56
Nanko et al^Citation47	1993	Japan	East Asian	Population based	–	–	–
Petronis et al^Citation48	1995	USA, Canada	Caucasian	Hospital based	–	–	–
Ohara et al^Citation49	1996	Japan	East Asian	Population based	34.40	0.99	1.37
Aguirre et al^Citation50	2007	Mexico	Indian	Population based	40.00		0.97
Mitsuyasu et al^Citation23,c	2007	Japan	East Asian	Hospital based	50.20	0.81	0.76
Daniels et al^Citation51	1994	UK	Caucasian	Hospital based	49.60	0.80	0.68
Sommer et al^Citation52	1993	Minnesota	Caucasian	Population based	65.00	0.44	1.61
Rao et al^Citation53	1994	USA	Caucasian	Population based	–	–	–
Hong et al^Citation54	1997	Taiwan	East Asian	Hospital based	28.70	0.68	0.62
Jonsson et al^Citation55	1996	Sweden	Caucasian	Population based	38.70	0.573	0.73
Rinetti et al^Citation56	2001	Mexico	Mestizos	Hospital based	–	–	–
Fujiwara et al^Citation57	1997	Japan	East Asian	Population based	–	–	–
Lung et al^Citation58	2006	Taiwan	East Asian	Population based	45.37	–	–
Nakamura et al^Citation59	1995	Japan	East Asian	Population based	–	–	–
Lung et al^Citation60	2009	Taiwan	East Asian	Population based	–	–	–
Fresan et al^Citation61	2007	Mexico	Caucasian	Population based	34.60	0.45	94.23
Zhang et al^Citation62	2003	China	East Asian	Population based	42.00	0.43	–
Tang et al^Citation68	2001	China	East Asian	Population based	33.00	0.44	0.40
Liang^Citation67	2005	China	East Asian	Population based	26.00	0.98	0.98
Zhao et al^Citation63	2005	China	East Asian	Population based	34.00	0.88	0.88
Zhao et al^Citation64	2006	China	East Asian	Population based	29.40	0.84	1.00
Chen et al^Citation65	2016	China	East Asian	Hospital based	39.19	0.81	0.89
Lu et al^Citation66	2003	China	East Asian	Population based	65.00	0.74	1.22
Serretti et al^Citation69	1999	Italy	Caucasian	Population based	–	–	–
Hong et al^Citation70	1998	Taiwan	East Asian	Hospital based	30.20	28.70	0.62
Catalano et al^Citation71	1993	Italy	Caucasian	Hospital based	46.90	30.00	1.34
Nakajima et al^Citation72	2007	Japan	East Asian	Population based	47.00	46.70	1.00
Okuyama et al^Citation22	1999	Japan	East Asian	Population based	47.10	47.90	0.63
Mitsuyasu et al^Citation75,d	2001	Japan	East Asian	Hospital based	51.50	50.50	0.75
Jonsson et al^Citation24	2001	Sweden	Caucasian	Population based	44.80	42.60	0.80
Pai et al^Citation73	2015	India	Indian	Population based	–	–	–
Xing et al^Citation18	2003	China	East Asian	Hospital based	41.20	41.80	–
Lai et al^Citation74	2010	China	East Asian	Hospital based	40.60	43.20	1.00
Zhong et al^Citation76	2010	China	East Asian	Population based	39.20	37.50	1.00
Tsutsumi et al^Citation19	2011	Japan	East Asian	Hospital based	47.20	42.10	0.50

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.

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 al^Citation42	1,006	270	1,182	322	232	1,044	282	1,222
Kohn et al^Citation43,a	–	–	–	–	22	76	52	238
Kohn et al^Citation43,b	–	–	–	–	13	85	17	101
Serretti et al^Citation44,Citation69	709	129	990	212	–	–	–	–
Hattori et al^Citation45	1,066	54	1,076	60	2	1,118	6	1,130
Tanaka et al^Citation46	134	6	133	7	0	140	2	138
Nanko et al^Citation47	148	12	152	10	2	158	0	162
Petronis et al^Citation48	77	23	154	46	21	79	32	168
Ohara et al^Citation49	286	20	227	15	18	288	10	232
Aguirre et al^Citation50	120	72	224	114	46	146	98	240
Mitsuyasu et al^Citation23,c	406	18	447	27	1	423	3	471
Daniels et al^Citation51	159	53	193	45	52	160	45	193
Sommer et al^Citation52	182	48	171	59	43	187	54	176
Rao et al^Citation53	39	17	31	9	17	39	8	32
Hong et al^Citation54	172	6	78	6	0	178	0	84
Jonsson et al^Citation55	187	49	124	28	42	194	23	129
Rinetti et al^Citation56	36	38	48	26	31	43	25	49
Fujiwara et al^Citation57	34	0	22	0	0	34	0	22
Lung et al^Citation58	1,216	44	846	10	3	1,257	0	856
Nakamura et al^Citation59	189	13	98	6	0	202	0	104
Lung et al^Citation60	1,774	54	838	8	0	1,828	0	846
Fresan et al^Citation61	88	54	285	119	47	95	104	300
Zhang et al^Citation62	131	3	145	7	0	134	0	152
Tang et al^Citation68	980	40	332	10	1	1,019	0	342
Liang^Citation67	176	26	185	25	4	198	2	208
Zhao et al^Citation63	78	246	75	249	3	321	6	318
Zhao et al^Citation64	41	121	40	136	0	162	3	173
Chen et al^Citation65	219	49	299	37	0	268	0	336
Lu et al^Citation66	155	5	157	3	1	159	0	160

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	I^Citation2	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

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	I^Citation2
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

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 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 al^Citation48	43	6	1	80	20	0	0.267	92.00	8.00	90.00	10.00
Ohara et al^Citation49	144	9	0	116	5	0	0.816	97.06	2.94	97.93	2.07
Serretti et al^Citation44,Citation69	184	28	0	225	37	1	0.689	0.93	0.07	0.93	0.07
Aguirre et al^Citation50	48	34	1	75	55	4	0.102	78.31	21.69	76.49	23.51
Mitsuyasu et al^Citation23,a	136	56	5	176	53	10	0.027	83.20	16.70	84.70	15.30
Kohn et al^Citation43,b	40	9	0	126	19	0	0.311	94.00	6.00	91.00	9.00
Kohn et al^Citation43,c	44	4	1	53	6	0	0.416	94.00	6.00	94.00	6.00
Hong et al^Citation54	68	10	2	35	7	0	0.556	91.25	8.75	91.70	8.30
Catalano et al^Citation71	76	3	0	69	6	0	0.718	98.10	1.90	96.00	4.00
Nakajima et al^Citation72	413	140	12	431	119	18	0.008	85.50	14.50	86.50	13.50

Notes: P_HWE, 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.

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 al^Citation23,a	10	75	129	13	87	139	0.898	77.80	22.20	76.40	23.60
Pai et al^Citation73	23	77	87	11	61	64	0.501	32.90	67.10	30.50	69.50
Xing et al^Citation18	20	77	113	28	98	80	0.816	27.90	72.10	37.40	62.60
Nakajima et al^Citation72	24	183	362	33	192	345	0.363	20.00	80.00	23.00	78.00
Tsutsumi et al^Citation19	24	138	248	16	158	211	0.041	22.68	77.32	24.68	75.32
Lai et al^Citation74	28	161	133	40	166	94	0.013	33.70	66.30	41.00	59.00

Notes: L, long allele; P_HWE, 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.

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 al^Citation22	58	125	69	38	142	89	0.119	48.00	52.00	41.00	59.00
Mitsuyasu et al^Citation23,a	33	106	67	31	115	93	0.623	41.75	58.25	37.05	62.95
Mitsuyasu et al^Citation75,b	25	122	61	25	110	75	0.109	41.30	58.70	38.10	61.90
Lung et al^Citation58	80	320	230	48	204	173	0.294	38.10	61.90	35.30	64.70
Jonsson et al^Citation24	23	74	35	60	205	118	0.061	45.50	54.50	42.00	58.00
Pai et al^Citation73	27	92	62	26	77	29	0.055	40.30	59.70	48.90	51.10
Xing et al^Citation18	37	103	70	25	111	70	0.059	42.10	57.90	39.10	60.90
Nakajima et al^Citation72	106	270	190	89	285	195	0.368	43.00	58.00	41.00	59.00
Lai et al^Citation74	87	115	120	81	95	124	–	44.88	55.12	42.83	57.17
Zhong et al^Citation76	62	78	60	53	64	83	–	45.91	54.09	42.50	57.50

Notes: P_HWE, 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.

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 al^Citation23,a	102	89	19	112	98	30	0.243	69.80	30.20	67.10	32.90
Mitsuyasu et al^Citation75,b	89	89	30	100	85	25	0.296	64.20	35.80	67.90	32.10
Xing et al^Citation18	83	100	27	91	102	13	0.025	63.30	36.70	68.90	31.10
Nakajima et al^Citation72	267	248	49	285	224	59	0.134	69.00	31.00	69.50	29.50
Lai et al^Citation74	161	113	48	166	102	32	0.009	67.55	32.45	72.33	27.67
Zhong et al^Citation76	112	77	31	107	68	25	0.010	68.41	31.59	70.50	29.50

Notes: P_HWE, 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.

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 al^Citation23,a	177	34	1	193	43	1	0.39	91.50	8.50	90.45	9.45
Mitsuyasu et al^Citation75,b	179	28	1	168	41	1	0.367	92.80	0.72	89.80	1.02
Xing et al^Citation74	137	66	7	127	74	5	0.126	81.00	19.00	79.60	20.40
Nakajima et al^Citation72	453	100	8	447	108	7	0.869	90.00	10.00	89.50	10.50

Notes: P_HWE, 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.

Figure 2 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 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 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 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 Funnel plot analysis for the detection of publication bias in the association between −521 C>T and schizophrenia.

Abbreviation: OR, odds ratio.

Figure 7 Funnel plot analysis for the detection of publication bias in the association between −616 C>G and schizophrenia.

Abbreviation: OR, odds ratio.

Figure 8 Funnel plot analysis for the detection of publication bias in the association between −376 C>T and schizophrenia.

Abbreviation: OR, odds ratio.

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