Glutathione S-Transferase M1/T1 Polymorphisms and Schizophrenia Risk: A New Method for Quality Assessment and a Systematic Review

Figures & data

Table 1 Data Extraction of Eligible Studies Included in the Meta-Analysis

Authors, Year, and Reference^Citation12–28	Country	Schizophrenia						Control
		GSTM1		GSTT1		GSTM1+GSTT1		GSTM1		GSTT1		GSTM1+GSTT1
		Null	Total	Null	Total	Null	Total	Null	Total	Null	Total	Null	Total
Ansari-Lari (2021)^Citation12	Iran	41	47	12	78	ND	ND	47	91	23	91	ND	ND
Nakamura (2015)^Citation13	Japan	303	640	273	640	ND	ND	337	622	268	622	ND	ND
Pejovic-Milovancevic (2016)^Citation14	Serbia	28	49	9	49	5	49	137	278	65	278	23	278
Pinheiro (2017)^Citation15	Brazil	28	54	13	54	9	54	36	78	10	78	3	78
Yan (2020)^Citation16	China	177	379	158	379	109	379	151	415	161	415	83	415
Zhang (2020)^Citation17	China	208	386	176	386	93	386	150	264	133	264	78	264
Rodríguez-Santiago (2009)^Citation18	Spain	243	594	142	645	ND	ND	289	585	105	593	ND	ND
Gravina (2011)^Citation19	Italy	82	138	25	138	10	138	70	133	30	133	21	133
Harada (2001)^Citation20	Japan	57	87	ND	ND	ND	ND	87	176	ND	ND	ND	ND
Kashani (2012)^Citation21	Iran	15	93	6	93	3	93	26	99	2	99	2	99
Matsuzawa (2009)^Citation22	Japan	129	214	88	214	ND	ND	119	220	80	220	ND	ND
Pae (2004)^Citation23	South Korea	70	111	ND	ND	ND	ND	61	130	ND	ND	ND	ND
Raffa (2013)^Citation24	Tunisia	79	138	59	138	39	138	63	123	67	123	30	123
Saadat (2007)^Citation25	Iran	ND	ND	52	292	ND	ND	ND	ND	99	292	ND	ND
Saruwatari (2013)^Citation26	Japan	77	154	68	154	40	154	99	203	99	203	45	203
Watanabe (2010)^Citation27	Japan	336	627	ND	ND	ND	ND	323	620	ND	ND	ND	ND
Kordi-Tamandani (2014)^Citation28	Iran	It was excluded due to methylation analysis of GSTT1
Total	——	1873	3711	1081	3260	308	1391	1995	4037	1142	3411	285	1593

Abbreviations: ND, no data; GSTM1, glutathione S-transferase mu 1; GSTT1, glutathione S-transferase theta 1.

Table 2 Stratification of Studies by Ethnicity, PCR Methods, Total Stars and Deductions Based on the Rewritten NOS

Authors	Population	Ethnicity	PCR Methods	Deductions	Total Stars
Ansari-Lari (2021)^Citation12	Iran	Caucasian	Multiplex PCR	No deduction	7
Nakamura (2015)^Citation13	Japan	East Asian	TaqMan qRT-PCR	One deduction	5
Pejovic-Milovancevic (2016)^Citation14	Serbia	Caucasian	Multiplex PCR	One deduction	5
Pinheiro (2017)^Citation15	Brazil	Caucasian	Multiplex RT-PCR	No deduction	7
Yan (2020)^Citation16	China	East Asian	Ordinary PCR	No deduction	6
Zhang (2020)^Citation17	China	East Asian	Multiplex PCR	No deduction	8
Rodríguez-Santiago (2009)^Citation18	Spain	Caucasian	MLPA	Two deductions	3
Gravina (2011)^Citation19	Italy	Caucasian	Multiplex PCR	No deduction	7
Harada (2001)^Citation20	Japan	East Asian	PCR/long fragment PCR	One deduction	7
Kashani (2012)^Citation21	Iran	Caucasian	Ordinary PCR	No deduction	5
Matsuzawa (2009)^Citation22	Japan	East Asian	PCR	No deduction	7
Pae (2004)^Citation23	South Korea	East Asian	PCR	No deduction	5
Raffa (2013)^Citation24	Tunisia	Caucasian	Multiplex PCR	No deduction	6
Saadat (2007)^Citation25	Iran	Caucasian	PCR	No deduction	6
Saruwatari (2013)^Citation26	Japan	East Asian	PCR	No deduction	7
Watanabe (2010)^Citation27	Japan	East Asian	TaqMan RT-PCR	One deduction	4

Abbreviations: PCR, polymerase chain reaction; qRT-PCR, quantitative real-time PCR; MLPA, multiplex ligation dependent probe amplification; GSTM1/T1, glutathione S-transferase mu 1 / theta 1; NOS, Newcastle-Ottawa quality assessment scale.

Figure 1 A flow diagram of the study selection process.

Figure 2 Forest plot of overall studies. (A) Analysis of null genotype vs present genotype of GSTM1. P = 0.25 [Overall OR = 1.11, 95% CI = (0.93–1.32)]. (B) Analysis of null genotype vs present genotype of GSTT1. P = 0.32 [Overall OR = 0.90, 95% CI = (0.73–1.11)]. (C) Analysis of null genotype vs present genotype of GSTM1 + GSTT1. P = 0.46 [Overall OR = 1.16, 95% CI = (0.79–1.69)].

Table 3 Overall Analysis and Subgroup Analysis of Ethnicity

Gene Symbols	Comparsions	Ethnicity	No. of Studies	Heterogeneity		Model	OR	95% CI	p
				p	I^2
GSTM1	Null type vs Present type	All	15	<0.0001	68%	Random	1.11	0.93–1.32	0.25
		Asian	8	0.0003	74%	Random	1.19	0.94–1.49	0.15
		Caucasian	7	0.04	55%	Random	1.00	0.75–1.33	0.98
GSTT1	Null type vs Present type	All	13	0.0002	68%	Random	0.90	0.73–1.11	0.32
		Asian	5	0.42	0%	Fixed	0.99	0.87–1.13	0.89
		Caucasian	8	<0.0001	78%	Random	0.85	0.55–1.31	0.46
GSTM1+GSTT1	Double null vs Present type	All	8	0.004	66%	Random	1.15	0.79–1.69	0.46
		Asian	3	0.008	79%	Random	1.16	0.71–1.89	0.56
		Caucasian	5	0.03	63%	Random	1.22	0.59–2.51	0.60

Abbreviations: GSTM1/T1, glutathione S-transferase mu 1/theta 1; OR, odds ratio; CI, confidence interval.

Table 4 Overall Analysis and Subgroup Analysis of PCR Methods

Gene Symbols	Comparsions	PCR Methods	No. of Studies	Heterogeneity		Model	OR	95% CI	p
				p	I^2
GSTM1	Null type vs Present type	All	15	<0.0001	68%	Random	1.11	0.93–1.32	0.25
		Multiplex PCR	8	0.35	10%	Fixed	1.17	1.00–1.37	0.05
		Others	7	<0.0001	81%	Random	1.02	0.76–1.36	0.91
GSTT1	Null type vs Present type	All	13	0.0002	68%	Random	0.90	0.73–1.11	0.32
		Multiplex PCR	8	0.02	58%	Random	0.73	0.56–0.94	0.02
		Others	5	0.18	36%	Fixed	1.14	0.98–1.32	0.08
GSTM1+GSTT1	Double null vs Present type	All	8	0.004	66%	Random	1.15	0.79–1.69	0.46
		Multiplex PCR	5	0.09	50%	Fixed	0.90	0.71–1.14	0.39
		Others	3	0.28	21%	Fixed	1.73	1.27–2.36	0.0006

Notes: p > 0.05, the difference is not statistically significant; p < 0.05, indicated in bold, the difference is statistically significant; p = 0.05, bold, the difference tends to be statistically significant, but need to further analysis.

Abbreviations: GSTM1/T1, glutathione S-transferase mu 1/theta 1; PCR, polymerase chain reaction; OR, odds ratio; CI, confidence interval.

Table 5 Overall Analysis and Subgroup Analysis of Stars Obtained from NOS

Gene Symbols	Comparsions	Stars of Rewritten NOS	No. of Studies	Heterogeneity		Model	OR	95% CI	p
				p	I^2
GSTM1	Null type vs Present type	All	15	<0.0001	68%	Random	1.11	0.93–1.32	0.25
		6–10 stars	9	0.25	22%	Fixed	1.24	1.08–1.43	0.002
		<=5 stars	6	0.001	76%	Random	0.95	0.72–1.25	0.70
GSTT1	Null type vs Present type	All	13	0.0002	68%	Random	0.90	0.73–1.11	0.32
		6–10 stars	9	0.0007	70%	Random	0.82	0.63–1.08	0.16
		<=5 stars	4	0.15	43%	Fixed	1.09	0.92–1.29	0.30
GSTM1+GSTT1	Double null vs Present type	All	8	0.004	66%	Random	1.15	0.79–1.69	0.46
		6–10 stars	6	0.001	76%	Random	1.13	0.73–1.75	0.58
		<=5 stars	2	0.81	0%	Fixed	1.34	0.56–3.24	0.51

Notes: p > 0.05, the difference is not statistically significant; p < 0.05, indicated in bold, the difference is statistically significant.

Abbreviations: GSTM1/T1, glutathione S-transferase mu 1/theta 1; OR, odds ratio; CI, confidence interval; NOS, Newcastle-Ottawa quality assessment scale.

Table 6 Overall Analysis and Subgroup Analysis of Deductions Assessed Using Rewritten NOS

Gene Symbols	Comparsions	Deductions	No. of Studies	Heterogeneity		Model	OR	95% CI	p
				p	I^2
GSTM1	Null type vs Present type	All	15	<0.0001	68%	Random	1.11	0.93–1.32	0.25
		No deductions	10	0.08	42%	Fixed	1.20	1.05–1.38	0.007
		Deductions	5	0.001	78%	Random	1.00	0.75–1.34	0.99
GSTT1	Null type vs Present type	All	13	0.0002	68%	Random	0.90	0.73–1.11	0.32
		No deductions	10	0.0005	70%	Random	0.85	0.65–1.12	0.26
		Deductions	3	0.18	42%	Fixed	1.08	0.91–1.28	0.39
GSTM1+GSTT1	Double null vs Present type	All	8	0.004	66%	Random	1.15	0.79–1.69	0.46
		No deductions	7	0.002	71%	Random	1.15	0.76–1.74	0.51
		Deductions	1	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable

Notes: p > 0.05, the difference is not statistically significant; p < 0.05, the difference is statistically significant. Not applicable: only one studies is not suitable for analysis.

Abbreviations: GSTM1/T1, glutathione S-transferase mu 1/theta 1; OR, odds ratio; CI, confidence interval; NOS, Newcastle-Ottawa quality assessment scale;

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