Front. Psychiatry Frontiers in Psychiatry Front. Psychiatry 1664-0640 Frontiers Media S.A. 10.3389/fpsyt.2022.976428 Psychiatry Systematic Review Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis Zhang Yu-Xin 1 2 † Yang Lu-Ping 3 † Gai Cong 1 Cheng Cui-Cui 1 Guo Zhen-yu 1 Sun Hong-Mei 1 Hu Die 1 * 1Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China 2Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China 3School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China

Edited by: Muhammad Muddassir Ali, University of Veterinary & Animal Sciences, Pakistan

Reviewed by: Furqan Awan, University of Veterinary & Animal Sciences, Pakistan; İbrahim Hakkı Ciğerci, Afyon Kocatepe University, Turkey

 *Correspondence: Die Hu, hudie0610@bucm.edu.cn

†These authors have contributed equally to this work

This article was submitted to Public Mental Health, a section of the journal Frontiers in Psychiatry

 18 08 2022 2022 13 976428 23 06 2022 28 07 2022 Copyright © 2022 Zhang, Yang, Gai, Cheng, Guo, Sun and Hu. 2022 Zhang, Yang, Gai, Cheng, Guo, Sun and Hu

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

 Background

Psychiatric disorders have seriously affected human life, one of the risk genes related to psychosis is the methylenetetrahydrofolatereductase (MTHFR) gene. This gene has a potential role in psychiatric disorders. Therefore, a meta-analysis is conducted to investigate the correlations between two prevalent MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T, A1298C, severe psychological disorders (schizophrenia, major depression, bipolar disorder).

 Methods

A total of 81 published studies were screened and selected by a search of electronic databases up to April 2022. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR polymorphism and psychiatric disorders susceptibility by using random effect models.

 Results

We found that MTHFR C677T polymorphism is significantly related to schizophrenia and major depression in the overall population. MTHFR C677T has been linked to an increased risk of bipolar disorder in the recessive model (TT vs. CT + CC). Ethnic subgroup analysis shows that schizophrenia and major depression significantly correlate with MTHFR C677T and A1298C in Asian populations but not Caucasians. Besides, schizophrenia is correlated substantially with MTHFR C677T in the African population. However, the MTHFR A1298C polymorphism is only marginally linked to major depression.

 Conclusion

Findings of the current study revealed that MTHFR may contribute to the common pathogenesis of psychiatric diseases and that its variants may be essential in controlling the expression of psychosis-related genes. This study could help the researchers and health specialists in the early diagnosis and treatment of psychiatric disorders.

 MTHFR C677T MTHFR A1298C disorders meta-analysis gene variants Introduction

Mental disorders have seriously affected human life, causing considerable familial and social burden (1). They are among the leading causes of disability globally and have been related to an increase in premature mortality (2). Major psychiatric disorders include schizophrenia (SZ), major depression (MD), bipolar disorder (BPD), and others (3). These mental disorders are more likely to occur in families, suggesting that they are related to genetic factors (4, 5). Many susceptible genes have been found through unbiased genome-wide association studies (GWAS), a kind of analysis comparing allele frequencies of all available polymorphic markers with specific symptoms or disease states (6, 7). GWAS and many other follow-up replication studies have suggested that methylenetetrahydrofolatereductase (MTHFR) polymorphisms are associated with psychiatric disorders.

The MTHFR is a crucial enzyme in the one-carbon metabolism (OCM) process, which involves folate and homocysteine (Hcy) metabolisms. It transforms 5,10-methylenetetrahydrofolate (5,10-methylene THF) to 5-methyltetrahydrofolate (5-methyl THF), and it is involved in folate and homocysteine conversion, which is linked to DNA methylation (8–10). A number of mutations in the MTHFR gene have been found, and the most common mutations are C677T (rs1801133) and A1298C (rs1801131), which are correlated with enzyme deficiency (11–14). In addition, MTHFR polymorphism may significantly decrease MTHFR activity, affect the concentration of Hcy in plasma, and lead to a wide range of mental, neurological, and vascular dysfunction (15).

The human Methylenetetrahydrofolatereductase (MTHFR) gene is located in chromosomal region 1p36.3 (16). The MTHFR gene has 14 common or rare single nucleotide polymorphisms linked with enzyme defects, the most prevalent of which are C677T and A1298C. The C677T gene location is one of the most researched and clinically significant variants in exon 4. The variation in C677T is due to the replacement of cytosine by thymine, which leads to the conversion of valine to alanine at codon 222 (11). The polymorphism of A1298C is due to the adenine substitution by cytosine, leading to the conversion of glutamic acid to alanine at residue 429 (10). The replacement of 677 and 1,298 nucleotides C-T and A-C in the MTHFR gene reduces enzyme activity, and this decrease in MTHFR activity may affect the OCM cycle (17). Abnormal OCM might impair cortical and hippocampal neurogenesis during development and affect brain maturation and function (18–20).

The association between MTHFR polymorphism and mental illnesses has already been explored, but the influence of MTHFR on psychiatric disorders is still disputed, and limited studies have been found (21–23). These inconsistencies might be attributed to limited sample sizes, ethnic heterogeneity, and differences in population substructure. So, in current study these limitations have been overcome and summarized the conflicting data. A meta-analysis is performed to explore the connection of MTHFR C677T and A1298C polymorphisms with major mental disorders (including SZ, MD, and BPD). We also assessed whether ethnicity would affect the results. Therefore, it will provide more powerful evidence of whether MTHFR variants influence psychiatric diseases.

 Materials and methods Search strategy

We initially searched PubMed, Embase, Proquest, Web of Science, CNKI (Chinese National Knowledge Infrastructure), VIP (Chinese) database, and Wanfang (Chinese) database for the following terms: MTHFR (methylenetetrahydrofolatereductase), gene (gene or genetic or polymorphism or variants or variation), and psychiatric disorders (psychiatry disorders or mental illness or mental disorders or psychosis). We discovered that most research concentrated on MTHFR C677T and MTHFR A1298C. The researchers investigated the relationships between MTHFR gene variants and susceptibility to mental diseases such as schizophrenia, bipolar disorder, and depression. To guarantee that we missed no studies, we searched these databases again using these gene terms (MTHFR C677T and A1298C) and major mental disorders such as “schizophrenia,” “bipolar disorder,” “depression,” and so on. All of the research was completed and published by April 2022. After that, we selected relevant papers and examined their bibliographies to find additional references.

 Study selection

Selection of articles for analysis purposes was made based on the following criteria: (1) case-control studies; (2) giving comprehensive data of formally diagnosed patients with unrelated healthy control subjects for generating an odds ratio (OR) with a 95% confidence interval (CI); (3) Case status was classified as having a DSM-IV-diagnosed mental condition, with control patients having no history of psychiatric disorders or other neurological abnormalities; (4) the studies used samples that did not overlap with other studies; (5) the use of internationally recognized loci gene polymorphism detection techniques (such as polymerase chain reaction-restriction fragment length polymorphism, real-time quantitative polymerase chain reaction, or amplification block mutation system-polymerase chain reaction); and (6) the demographic characteristics of the control group, such as gender and age, were comparable to those of the case group. In addition, articles were excluded if they (1) not reported the target genotype frequencies, (2) were reviews, letters, or commentaries, or (3) were duplicate reports.

 Data extraction and management

Two reviewers independently extracted the following information from all eligible studies: author, year of publication, country, ethnicity (categorized as Asian, Caucasian, and African populations), and the number of distinct genotypes in cases and controls for C677T or A1298C genotype. In the case of a disagreement, a discussion was held, and if no agreement could be achieved, a third person was consulted for consensus.

 Statistical analysis

We investigated the potential of conducting a meta-analysis of all eligible studies. The odds ratio (OR) and associated 95% confidence intervals (CIs) were used to examine the strength of the connection between MTHFR polymorphism and mental disorders: the allele model (T vs. C, C vs. A), the dominant model (TT + CT vs. CC, CC + AC vs. AA), the homozygote model (TT vs. CC, CC vs. AA) and the recessive model (TT vs. CT + CC, CC vs. AC + AA). The Chi-square test was used to analyze the genotype distribution in the control groups for Hardy Weinberg equilibrium (HWE). The Cochran’s (Q) X2 test and I2 statistic were used to assess the heterogeneity between individual studies (24). Considering the heterogeneity of studies, this meta-analysis adopted a random effect model (25). Subgroup analyses were performed using ethnicity stratification, and sensitivity analyses were undertaken by excluding papers from the meta-analysis that were not in HWE. The funnel plots were displayed and evaluated using Egger’s linear regression test to control publication bias (26). Stata 14.0 was used to conduct all statistical analyses (StataCorp, College Station, TX, United States). A P-value of less than 0.05 was regarded as statistically significant. The article mainly showed the forest plots of T vs. C of MTHFR C677T and C vs. A of MTHFR A1298C; the other results were shown in the tables.

 Results Characteristics of eligible studies

Out of screened articles, 843 unduplicated association studies were found. Figure 1 depicts a flow chart of the research process, the eliminated studies, and the reasons for their exclusion. Following an initial literature search and further screening, 81 (27–106) publications were retrieved. Our meta-analysis comprised 49,775 subjects (20,981 patients and 28,794 controls) with MTHFR C677T genotyping and 16,058 subjects (6,690 patients and 9,368 controls) with MTHFR A1298C genotyping. Detailed information (first author, year of publication, country, ethnicity, case/control, genotype, and PHWE) of included articles are summarized in Tables 1, 2.

Flow diagram of the study selection process.

Overview of MTHFR C677T genotype distribution of psychosis patients and controls, with information about country, ethnicity, and disease.

References Year Country Ethnicity Case Control Case
 Control
 PHWE
CC CT TT CC CT TT
Schizophrenia
Arinami et al. (27) 1997 Japanese Asian 297 419 96 138 63 154 214 51 0.074
Kunugi et al. (28) 1998 Japanese Asian 343 258 121 168 54 95 129 34 0.342
Virgos et al. (29) 1999 Spain Caucasian 210 218 81 98 31 79 106 33 0.793
Joober et al. (30) 2000 Canada Caucasian 105 90 30 52 23 41 36 13 0.278
Sazci et al. (31) 2003 Turkey Caucasian 130 226 59 49 22 106 103 17 0.236
Tan et al. (32) 2004 Singapore Asian 236 120 136 84 16 80 33 7 0.165
Yu et al. (33) 2004 China Asian 230 251 91 96 43 85 126 40 0.554
Yu et al. (33) 2004 Scotland Caucasian 426 628 199 186 41 306 260 62 0.535
Sazci et al. (34) 2005 Turkey Asian 297 341 144 115 38 161 156 24 0.093
Vilella et al. (35) 2005 Spain Caucasian 158 234 58 75 25 85 85 39 0.952
Kempisty et al. (36) 2006 Poland Caucasian 200 300 113 68 19 210 79 11 0.303
Philibert et al. (37) 2006 United States Caucasian 206 359 107 83 16 176 137 46 0.021*
Lee et al. (38) 2006 South Korea Asian 235 235 74 128 33 99 115 21 0.009*
Yang et al. (39) 2007 China Asian 100 100 33 51 16 52 40 8 0.937
Jonsson et al. (40) 2008 Denmark Caucasian 419 1006 200 177 42 490 413 103 0.249
Jonsson et al. (40) 2008 Norway Caucasian 163 177 75 70 18 80 75 22 0.501
Jonsson et al. (40) 2008 Sweden Caucasian 258 293 137 104 17 156 113 24 0.581
Muntjewerff (41) 2008 Netherlands Caucasian 252 405 110 111 31 205 165 35 0.61
Roffman et al. (42) 2008 United States Caucasian 79 75 41 27 11 35 32 8 0.865
Feng et al. (43) 2009 China Asian 123 123 17 67 39 40 65 18 0.308
Betcheva et al. (44) 2009 Bulgaria Caucasian 185 182 76 85 24 84 76 22 0.457
García-Miss et al. (45) 2010 Mexico Caucasian 105 108 29 45 31 22 54 31 0.864
Kang et al. (46) 2010 Korean Asian 360 348 125 176 59 130 158 60 0.317
Ye et al. (47) 2010 China Asian 104 56 12 58 34 14 32 10 0.266
Bouaziz et al. (48) 2010 Tunisia African 25 25 18 4 3 19 5 1 0.397
Arzaghi et al. (49) 2011 Iran Asian 66 94 35 27 4 54 38 2 0.11
Kim et al. (50) 2011 Korean Asian 201 350 62 101 38 112 167 71 0.313
Muntjewerff et al. (51) 2011 Netherlands Caucasian 739 886 334 319 86 405 389 92 0.921
Tsutsumi et al. (52) 2011 Japan Asian 413 385 160 184 69 138 183 64 0.8
Zhang et al. (53) 2012 China Asian 235 102 96 113 26 52 45 5 0.225
Lochman et al. (54) 2013 Czechia Caucasian 186 209 72 90 24 105 86 18 0.948
Zhang et al. (55) 2013 China Asian 1002 1036 166 450 384 213 505 318 0.63
Kontis et al. (56) 2013 Greece Caucasian 90 55 40 37 13 21 22 12 0.187
El-Hadidy et al. (57) 2014 Egypt African 103 149 52 36 15 114 30 5 0.103
Hei et al. (58) 2014 China Asian 130 80 17 65 48 24 38 18 0.029
Nishi et al. (59) 2014 Japan Asian 621 486 220 309 92 174 239 73 0.532
Nishi et al. (59) 2014 Japan Asian 1,149 2,742 417 530 202 1,072 1,260 410 0.207
Foroughmand et al. (60) 2015 Iran Asian 200 200 104 76 20 123 64 13 0.244
Misiak et al. (61) 2016 Poland Caucasian 135 146 64 52 16 71 53 22 0.786
Takano et al. (62) 2016 Japan Asian 45 30 17 18 10 12 14 4 0.62
Wang et al. (63) 2017 China Asian 254 339 79 129 46 109 175 55 0.26
Oniki et al. (64) 2017 Japan Asian 256 194 89 135 32 64 93 37 0.207
Debost et al. (65) 2017 Denmark Caucasian 1699 1681 839 704 156 829 724 128 0.08
Zhilyaeva et al. (66) 2018 Russia Caucasian 500 499 245 212 43 280 188 31 0.057
Ota et al. (67) 2019 Japan Asian 538 1263 181 255 102 458 604 201 0.937
Wan et al. (68) 2019 China Asian 97 92 24 47 26 24 43 25 0.532
Wan, L (69) 2019 China Asian 242 234 45 122 75 71 113 50 0.687
Major depression
Arinami et al. (27) 1997 Japanese Asian 32 419 9 14 9 154 214 51 0.074
Kunugi et al. (28) 1998 Japanese Asian 71 258 10 31 30 95 129 34 0.342
Tan et al. (32) 2004 Singapore Asian 88 120 49 34 5 80 33 7 0.165
Kelly et al. (70) 2004 United Kingdom Caucasian 100 89 30 56 14 40 37 12 0.467
Reif et al. (71) 2005 Germany Caucasian 46 176 23 17 6 75 80 21 0.962
Yuan et al. (72) 2005 China Asian 60 80 22 27 11 27 38 15 0.801
Chen-Sheng et al. (73) 2005 China Asian 39 20 22 15 2 11 9 0 0.194
Yuan (74) 2007 China Asian 60 80 22 27 11 27 38 15 0.801
Słopien et al. (75) 2008 Poland Caucasian 83 89 26 38 19 46 36 7 0.991
Zhao (76) 2008 China Asian 77 85 12 37 28 21 48 16 0.219
Yuan et al. (77) 2008 China Asian 116 80 46 48 22 27 38 15 0.801
Hong et al. (78) 2009 China Asian 178 85 75 84 19 32 44 9 0.28
Kim et al. (79) 2009 China Asian 63 458 16 28 19 84 248 126 0.63
Pan et al. (80) 2009 United States Caucasian 170 83 72 79 19 30 44 9 0.598
Cao et al. (81) 2010 China Asian 50 59 9 23 18 24 27 8 0.926
Zeman et al. (82) 2010 Czechia Caucasian 42 41 15 18 9 16 17 8 0.377
Feng et al. (83) 2010 China Asian 152 152 32 66 54 51 81 20 0.167
Li et al. (84) 2010 China Asian 402 600 132 192 78 156 343 101 <0.001*
Song (85) 2010 China Asian 156 123 33 68 55 35 74 14 0.008*
Lizer et al. (86) 2011 United States Caucasian 82 74 31 34 17 33 28 13 0.114
Zhao et al. (87) 2011 China Asian 94 98 24 43 27 36 45 17 0.651
Chojnicka et al. (88) 2012 Poland Caucasian 710 2547 342 300 68 1213 1081 253 0.593
Evinova et al. (89) 2012 Slovak Caucasian 134 143 70 54 10 58 73 12 0.1
Qiao et al. (90) 2012 China Asian 94 98 24 43 27 36 45 17 0.651
Shen et al. (91) 2014 China Asian 368 219 88 259 21 113 91 15 0.563
Sayadi et al. (92) 2016 Tunisia African 208 187 105 80 23 80 93 14 0.066
Mei et al. (93) 2016 China Asian 37 65 9 26 2 32 27 6 0.59
Huang et al. (94) 2017 China Asian 80 80 20 36 24 30 38 12 0.995
Li et al. (95) 2017 China Asian 218 582 97 93 28 461 89 32 <0.001*
Mei et al. (96) 2018 China Asian 106 175 25 75 6 90 73 12 0.59
Saraswathy et al. (97) 2019 India African 91 206 78 12 1 183 22 1 0.68
Bipolar disorder
Arinami et al. (27) 1997 Japanese Asian 40 419 15 20 5 154 214 51 0.074
Kunugi et al. (28) 1998 Japanese Asian 143 258 41 74 28 95 129 34 0.342
Tan et al. (32) 2004 Singapore Asian 167 120 99 60 8 80 33 7 0.165
Reif et al. (71) 2005 Germany Caucasian 92 176 48 34 10 75 80 21 0.962
Kempisty et al. (36) 2006 Poland Caucasian 200 300 108 73 19 210 79 11 0.303
Zhao et al. (98) 2008 China Asian 61 73 12 28 21 18 40 15 0.404
Ozbek et al. (99) 2008 Turkey Caucasian 197 238 104 76 17 116 97 25 0.603
Jonsson et al. (40) 2008 Norway Caucasian 117 177 58 49 10 80 75 22 0.501
Chen et al. (100) 2009 China Asian 501 461 178 231 92 153 235 73 0.272
Ezzaher et al.(101) 2011 Tunisia African 92 170 41 40 11 94 62 14 0.411
Arzaghi et al. (49) 2011 Iran Asian 90 94 52 34 4 54 38 2 0.11
El-Hadidy et al. (57) 2013 Egypt African 134 149 46 70 18 114 30 5 0.239
Permoda-Osip et al. (102) 2014 Poland Caucasian 112 164 51 50 11 66 82 16 0.657
Wang et al. (103) 2015 China Asian 531 447 287 206 38 215 199 33 0.16
Rahimi et al. (104) 2016 Iran Caucasian 150 148 69 67 14 81 62 5 0.093

*P < 0.05.

Overview of MTHFR A1298C genotype distribution of psychosis patients and controls, with information about country, ethnicity, and disease.

First author Year Country Ethnicity Case Control Case
 Control
 PHWE
AA AC CC AA AC CC
Schizophrenia
Sazci et al. (31) 2003 Turkey Caucasian 130 226 57 59 14 114 93 19 0.996
Yu et al. (33) 2004 China Asian 230 251 130 78 22 154 81 16 0.235
Scotland Caucasian 426 628 177 209 40 292 272 64 0.955
Sazc et al. (34) 2005 Turkey Caucasian 297 341 130 129 38 159 155 27 0.201
Vilella et al. (35) 2005 Spain Caucasian 158 234 76 68 14 124 97 13 0.286
Lee et al. (38) 2006 South Korea Asian 235 236 157 7 71 145 14 77 <0.001*
Kempisty et al. (105) 2007 Poland Caucasian 200 300 109 74 17 185 105 10 0.29
Jonsson et al. (40) 2008 Denmark Caucasian 418 1004 184 186 48 462 419 123 0.052
2008 Norway Caucasian 163 177 89 60 14 82 79 16 0.625
2008 Sweden Caucasian 258 293 110 113 35 122 129 42 0.406
Betcheva et al. (44) 2009 Bulgaria Caucasian 181 183 91 72 18 80 79 24 0.406
Kang et al. (46) 2010 Korean Asian 360 348 248 105 7 239 100 9 0.703
Zhang et al. (106) 2010 China Asian 379 380 230 127 22 260 108 12 0.848
Kim et al. (50) 2011 Korean Asian 201 350 129 67 5 240 105 5 0.083
Zhang et al. (53) 2012 China Asian 235 102 126 91 18 62 33 7 0.376
Foroughmand et al. (60) 2015 Iran Asian 200 200 65 108 27 60 89 51 0.126
Misiak et al. (61) 2016 Poland Caucasian 135 146 55 64 13 55 72 19 0.64
Takano et al. (62) 2016 Japan Asian 45 30 34 8 3 21 9 0 0.2
Oniki et al. (64) 2017 Japan Asian 256 194 173 75 8 124 65 5 0.597
Ota et al. (67) 2019 Japan Asian 537 1262 358 163 16 820 395 47 0.947
Wan et al. (68) 2019 China Asian 97 92 66 29 2 69 22 1 0.603
Wan et al. (69) 2019 China Asian 242 234 174 63 5 171 58 5 0.975
Major depression
Reif et al. (71) 2005 Germany Caucasian 46 184 16 21 9 75 96 13 0.016*
Zeman et al. (82) 2010 Czechia Caucasian 42 41 22 17 3 20 18 3 0.495
Feng et al. (83) 2010 China Asian 152 152 122 28 2 115 35 2 0.716
Evinova et al. (89) 2012 Slovak Caucasian 134 143 49 65 20 70 61 12 0.801
Li et al. (95) 2017 China Asian 218 582 86 75 57 396 144 42 <0.001*
Bipolar disorder
Reif et al. (71) 2005 Germany Caucasian 92 184 30 47 15 75 96 13 0.016*
Kempisty et al. (105) 2007 Poland Caucasian 200 300 99 78 23 185 105 10 0.29
Jonsson et al. (40) 2008 Norway Caucasian 115 177 47 56 12 82 79 16 0.624
Ozbek et al. (99) 2008 Turkey Caucasian 197 238 91 84 22 113 101 24 0.848
Permoda-Osip et al. (102) 2014 Poland Caucasian 111 156 51 50 10 60 74 22 0.915

*P < 0.05.

 Methylenetetrahydrofolatereductase C677T/A1298C and psychiatric disorders Association between the methylenetetrahydrofolatereductase C677T/A1298C polymorphisms and schizophrenia

Findings of the association and the heterogeneity test is shown in Table 3. MTHFR C677T polymorphism was shown to be highly associated with an increased risk of developing SZ in all statistical models (for T vs. C, OR = 1.16, 95% CI = 1.10–1.23, P < 0.001; for TT + CT vs. CC: OR = 1.18, 95% CI = 1.10–1.27, P < 0.001; for TT vs. CT + CC: OR = 1.25, 95% CI = 1.13–1.37, P < 0.001; for TT vs. CC: OR = 1.35, 95% CI = 1.19–1.52, P < 0.001) (Figure 2 and Table 3).

Odds ratios and heterogeneity results for the 4 genetic models of the MTHFR C677T and A1298C for SZ.

MTHFR Comparison model OR (95% CI) POR Heterogeneity
Q within P-value I2 (%)
MTHFRC677T All studies T vs. C 1.16(1.10–1.23) <0.001 116.30 <0.001 60.4
TT + CT vs. CC 1.18(1.10–1.27) <0.001 93.38 <0.001 50.7
TT vs. CT + CC 1.25(1.13–1.37) <0.001 80.44 0.001 42.8
TT vs. CC 1.35(1.19–1.52) <0.001 103.78 <0.001 55.7
Asian T vs. C 1.19(1.11–1.29) <0.001 56.46 <0.001 57.5
TT + CT vs. CC 1.22(1.10–1.35) <0.001 48.36 0.002 50.4
TT vs. CT + CC 1.31(1.16–1.48) <0.001 41.63 0.014 42.3
TT vs. CC 1.46(1.24–1.72) <0.001 57.48 <0.001 58.2
Caucasian T vs. C 1.09(1.01–1.17) 0.036 35.29 0.013 46.2
TT + CT vs. CC 1.11(1.01–1.21) 0.034 28.48 0.075 33.3
TT vs. CT + CC 1.12(0.97–1.29) 0.132 27.76 0.088 31.6
TT vs. CC 1.16(0.98–1.37) 0.082 32.08 0.031 40.8
African T vs. C 2.58(1.45–4.57) 0.001 1.36 0.243 26.6
TT + CT vs. CC 2.37(1.00–5.64) 0.050 1.84 0.175 45.6
TT vs. CT + CC 4.59(1.77–11.92) 0.002 0.10 0.756 0
TT vs. CC 5.81(1.20–15.32) <0.001 0.31 <0.001 0
MTHFR A1298C All studies C vs. A 1.04(0.96–1.13) 0.305 33.40 0.042 37.1
CC + AC vs. AA 1.06(0.98–1.15) 0.165 23.60 0.313 11.0
CC vs. AC + AA 1.05(0.88–1.25) 0.622 31.24 0.07 32.8
CC vs. AA 1.08(0.89–1.29) 0.438 31.32 0.069 32.9
Caucasian C vs. A 1.05(0.95–1.17) 0.327 14.04 0.121 35.9
CC + AC vs. AA 1.07(0.95–1.20) 0.289 11.04 0.273 18.5
CC vs. AC + AA 1.09(0.87–1.37) 0.434 13.54 0.14 33.5
CC vs. AA 1.12(0.88–1.44) 0.357 14.85 0.095 39.4
Asian C vs. A 1.03(0.92–1.16) 0.602 18.98 0.061 42.0
CC + AC vs. AA 1.05(0.94–1.18) 0.418 12.42 0.333 11.5
CC vs. AC + AA 1.00(0.74–1.34) 0.981 16.80 0.114 34.5
CC vs. AA 1.02(0.77–1.37) 0.870 15.70 0.153 29.9

Forest plots for the associations between MTHFR C677T polymorphisms and SZ for the allele model with random effect model.

An ethnic subgroup analysis revealed a substantial association between MTHFR C677T polymorphism and SZ among Asian populations (for T vs. C: OR = 1.19, 95% CI = 1.11–1.29, P < 0.001; for TT + CT vs. CC: OR = 1.22, 95% CI = 1.10–1.35, P < 0.001; for TT vs. CT + CC: OR = 1.31, 95% CI = 1.16–1.48, P < 0.001; for TT vs. CC: OR = 1.46, 95% CI = 1.24–1.72, P < 0.001); in Caucasian populations, a significant association was found with the allele model (for T vs. C: OR = 1.09, 95% Cl = 1.01–1.17, P = 0.036) and the dominant model (for TT + CT vs. CC: OR = 1.11, 95% Cl = 1.01–1.21, P = 0.034); in African populations, there was a significant association with the allele model (for T vs. C: OR = 2.58, 95% Cl = 1.45–4.57, P = 0.001), the recessive model (TT vs. CT + CC: OR = 4.59, 95% CI = 1.77–11.92, P = 0.002) and the homozygote model (for TT vs. CC: OR = 5.81, 95% Cl = 1.20–15.32, P < 0.001). All these findings are summarized in Table 3. Subgroup analysis reveals that the association between MTHFR C677T polymorphism and SZ exists in Asian (all genetic models) and African populations (allele models, recessive models, and homozygous models) but not in Caucasian (only allele models and dominant models).

The MTHFR A1298C polymorphism was not statistically correlated with SZ in all models (Figure 3 and Table 3). Moreover, subgroup analysis revealed no correlation between the MTHFR A1298C polymorphism and SZ in Asian or Caucasian populations (Figure 3 and Table 3). African populations were not included in the study because of the small number of studies.

Forest plots for the associations between MTHFR A1298C polymorphisms and SZ for the allele model with random effect model.

There were two articles not in Hardy–Weinberg equilibrium (37, 38) (Tables 1, 2). Sensitivity analysis revealed that the overall association between MTHFR C677T polymorphism and SZ remained unchanged after omitting these two samples from the meta-analysis (for T vs. C: OR = 1.17, 95% CI = 1.10–1.24, P < 0.001, Supplementary Figure 6; for TT + CT vs. CC: OR = 1.18, 95% CI = 1.10–1.28, P < 0.001; for TT vs. CT + CC: OR = 1.25, 95% CI = 1.14–1.38, P < 0.001; for TT vs. CC: OR = 1.35, 95% CI = 1.20–1.53, P < 0.001). Sensitivity analysis for the MTHFR A1298C polymorphism revealed that excluding Lee et al. (38) had no impact on the conclusion of the meta-analysis (Supplementary Figure 7).

 Association between the methylenetetrahydrofolatereductase C677T/A1298C polymorphisms and major depression

Table 4 shows the main results as well as the heterogeneity test. MTHFR C677T polymorphism was shown to be highly associated with an increased risk of developing MD in all statistical models (for T vs. C: OR = 1.33, 95% CI = 1.15–1.55, P < 0.001; for TT + CT vs. CC: OR = 1.35, 95% CI = 1.08–1.70, P = 0.009; for TT vs. CT + CC: OR = 1.58, 95% CI = 1.28–1.95, P < 0.001; for TT vs. CC: OR = 1.66, 95% CI = 1.31–2.11, P < 0.001) (Figure 4 and Table 4).

Odds ratios and heterogeneity results for the 4 genetic models of the MTHFR C677T and A1298C for MD.

MTHFR Comparison model OR (95% CI) POR Heterogeneity
Q within P-value I2 (%)
MTHFRC677T All studies T vs. C 1.33(1.15–1.55) <0.001 159.05 <0.001 81.1
TT + CT vs. CC 1.35(1.08–1.70) 0.009 183.95 <0.001 83.7
TT vs. CT + CC 1.58(1.28–1.95) <0.001 75.2 <0.001 60.1
TT vs. CC 1.66(1.31–2.11) <0.001 80.47 <0.001 62.7
Asian T vs. C 1.46(1.21–1.77) <0.001 107.45 <0.001 81.4
TT + CT vs. CC 1.52(1.11–2.08) 0.009 135.03 <0.001 85.2
TT vs. CT + CC 1.75(1.34–2.28) <0.001 54.54 <0.001 63.3
TT vs. CC 1.89(1.40–2.57) <0.001 56.63 <0.001 64.7
Caucasian T vs. C 1.09(0.88–1.34) 0.445 17.97 0.012 61.0
TT + CT vs. CC 1.08(0.81–1.44) 0.616 18.02 0.012 61.2
TT vs. CT + CC 1.07(0.86–1.34) 0.527 7.11 0.417 1.6
TT vs. CC 1.20(0.83–1.73) 0.337 11.59 0.115 39.6
African T vs. C 0.98(0.72–1.32) 0.879 1.07 0.301 6.5
TT + CT vs. CC 0.91(0.52–1.59) 0.735 1.95 0.162 48.8
TT vs. CT + CC 1.57(0.80–3.09) 0.189 0.07 0.788 0
TT vs. CC 1.30(0.65–2.63) 0.460 0.18 0.669 0
MTHFRA1298C All studies C vs. A 1.44(0.84–2.48) 0.191 35.80 <0.001 88.8
CC + AC vs. AA 1.42(0.77–2.61) 0.263 26.32 <0.001 84.8
CC vs. AC + AA 2.63(1.49–4.65) 0.001 7.55 0.109 47
CC vs. AA 2.83(1.39–5.77) 0.004 10.27 0.036 61
Caucasian C vs. A 1.40(1.08–1.82) 0.011 1.83 0.4 0
CC + AC vs. AA 1.39(0.97–1.98) 0.073 1.74 0.418 0
CC vs. AC + AA 2.14(1.23–3.71) 0.007 1.68 0.433 0
CC vs. AA 2.36(1.31–4.26) 0.004 1.58 0.454 0
Asian C vs. A 1.61(0.42–6.17) 0.484 23.67 <0.001 95.8
CC + AC vs. AA 1.61(0.39–6.68) 0.513 20.23 <0.001 95.1
CC vs. AC + AA 2.93(0.76–11.29) 0.118 2.16 0.142 53.7
CC vs. AA 3.13(0.53–18.66) 0.210 3.34 0.068 70

Forest plots for the associations between MTHFR C677T polymorphisms and MD for the allele model with random effect model.

Subgroup analysis by ethnicity revealed a substantial correlation between the MTHFR C677T polymorphism and MD in Asian populations (for T vs. C: OR = 1.46, 95% CI = 1.21–1.77, P < 0.001; for TT + CT vs. CC: OR = 1.52, 95% CI = 1.11–2.08, P = 0.009; for TT vs. CT + CC: OR = 1.75, 95% CI = 1.34–2.28, P < 0.001; for TT vs. CC: OR = 1.89, 95% CI = 1.40–2.57, P < 0.001), but not in Caucasian and African populations (Figure 4 and Table 4).

The MTHFR A1298C polymorphism was found to be highly associated with MD in the recessive model (for CC vs. AC + AA: OR = 2.63, 95% CI: 1.49–4.65, P = 0.001) and the homozygote model (for CC vs. AA: OR = 2.83, 95% Cl = 1.39–5.77, P = 0.004) (Table 4). Moreover, subgroup analysis demonstrated a positive correlation between the MTHFR A1298C polymorphism and MD in the Caucasian population (for C vs. A: OR = 1.40, 95% CI = 1.08–1.82, P = 0.011; for CC vs. AC + AA: OR = 2.14, 95% CI = 1.23–3.71, P = 0.007; for CC vs. AA: OR = 2.36, 95% CI = 1.31–4.26, P = 0.004) (Figure 5 and Table 4). Nonetheless, there was no statistical correlation between A1298C polymorphism and MD in Asian populations (Figure 5 and Table 4). Subgroup analysis shows that the correlation between MTHFR C677T polymorphism and MD exists in the Asian population (all genetic models) but not in Caucasian and African populations.

Forest plots for the associations between MTHFR A1298C polymorphisms and MD for the allele model with random effect model.

Four articles were not found in Hardy–Weinberg equilibrium (71, 84, 85, 95) (Tables 1, 2). Sensitivity analysis revealed that the overall correlation between MTHFR C677T polymorphism and MD remained unchanged after eliminating these data from the meta-analysis (Supplementary Figure 8). Sensitivity analyses for MTHFR A1298C polymorphism revealed that excluding Reif A. et al. (71) and Li et al. (95) resulted in a decreasing statistical correlation with MD; nonetheless, all statistical models revealed that MTHFR A1298C polymorphism was not significantly correlated with MD (Supplementary Figure 9).

 Association between the methylenetetrahydrofolatereductase C677T/A1298C polymorphisms and bipolar disorder

Table 5 displays the main results and the heterogeneity test. There was a marginal correlation between the MTHFR C677T polymorphism and BPD in the recessive model (for TT vs. CT + CC: OR = 1.31, 95% CI: 1.03–1.67, P = 0.028) and the homozygote model (for TT vs. CC: OR = 1.40, 95% Cl = 1.00–1.94, P = 0.049) (Table 5). Moreover, subgroup analysis indicated no statistical correlation between the MTHFR C677T polymorphism and BPD in Asian, African, or Caucasian populations (Figure 6 and Table 5). Additionally, all models revealed that the MTHFR A1298C polymorphism was not statistically correlated with BPD (Figure 7 and Table 5).

Odds ratios and heterogeneity results for the 4 genetic models of the MTHFR C677T and A1298C for BPD.

MTHFR Comparison model OR (95% CI) POR Heterogeneity
Q within P-value I2 (%)
MTHFRC677T All studies T vs. C 1.20(0.98–1.46) 0.073 76.32 <0.001 81.7
TT + CT vs. CC 1.21(0.93–1.57) 0.161 74.99 <0.001 81.3
TT vs. CT + CC 1.31(1.03–1.67) 0.028 22.71 0.065 38.4
TT vs. CC 1.40(1.00–1.94) 0.049 36.79 0.001 61.9
Asian T vs. C 1.07(0.92–1.24) 0.399 9.26 0.160 35.2
TT + CT vs. CC 1.01(0.83–1.23) 0.926 8.6 0.197 30.2
TT vs. CT + CC 1.23(0.99–1.54) 0.063 4.61 0.60 0
TT vs. CC 1.17(0.91–1.49) 0.216 6.03 0.42 0.4
Caucasian T vs. C 1.06(0.78–1.43) 0.711 23.61 <0.001 78.8
TT + CT vs. CC 1.03(0.73–1.46) 0.862 18.96 0.002 73.6
TT vs. CT + CC 1.20(0.73–1.98) 0.468 11.67 0.04 57.2
TT vs. CC 1.19(0.65–2.18) 0.566 15.96 0.007 68.7
African T vs. C 2.44(0.83–7.12) 0.104 14.29 <0.001 93.0
TT + CT vs. CC 3.09(0.79–12.18) 0.106 14.15 <0.001 92.9
TT vs. CT + CC 2.50(0.87–7.19) 0.09 2.59 0.107 61.4
TT vs. CC 3.90(0.81–18.69) 0.089 5.29 0.021 81.1
MTHFRA1298C All studies (Caucasian) C vs. A 1.19(0.91–1.56) 0.208 13.67 0.008 70.7
CC + AC vs. AA 1.19(0.91–1.56) 0.200 7.54 0.110 0.110
CC vs. AC + AA 1.50(0.81–2.77) 0.200 13.66 0.008 70.7
CC vs. AA 1.58(0.79–3.16) 0.200 15.85 0.003 74.8

Forest plots for the associations between MTHFR C677T polymorphisms and BPD for the allele model with random effect model.

Forest plots for the associations between MTHFR A1298C polymorphisms and BPD for the allele model with random effect model.

Only one study was not in Hardy Weinberg equilibrium (71) (Table 2), and there was no statistical association between A1298C polymorphism and BPD after removing this study (Supplementary Figure 10).

 Association between the methylenetetrahydrofolatereductase C677T/A1298C polymorphisms and psychiatric disorders

Significant publication biases were found when all diseases were considered (Supplementary Figure 5 and Supplementary Table 2). Therefore, analyses between MTHFR C677T and mental disorders were unsuitable here. However, the main results and the heterogeneity tests between MTHFR C677T and mental disorders were shown in Supplementary Table 1. Furthermore, the forest plots indicated that MTHFR C677T was strongly associated with psychiatric disorders, and sensitivity analysis did not affect the results (Supplementary Figures 1, 2).

Most studies were not in Hardy–Weinberg equilibrium when all diseases were considered. Moreover, analysis between MTHFR A1298C and psychiatric disorders was also unsuitable. Significant correlations were detected between the MTHFR A1298C polymorphism and psychiatric disorders (Supplementary Figure 3). However, sensitivity analysis revealed that excluding did change the conclusion (Supplementary Figure 4).

 Publication bias

In order to evaluate publication bias, we used formal statistical methods (Egger’s regression test). Table 6 and Figure 8 presented the funnel plots for the meta-analysis. We observed that for SZ, no publication bias could be observed except in the dominant model (TT + CT vs. CC, PEgger = 0.01). The Egger’s test results for MD were substantial in two genetic models of overall populations (allele model: C vs. A, PEgger = 0.03; homozygote model: CC vs. AA, PEgger = 0.02). And there was no publication bias for BPD. Publication bias may correlate to the editor’s decision for publication. However, it is common that only the positive results are published, and negative findings are unavailable. So, we could not exclude this kind of possibility.

Publication bias risk in this meta-analysis.

Disease MTHFR PEgger 95% CL
Schizophrenia C677T T vs. C 0.05 0.02-2.10
TT + CT vs. CC 0.01 0.27-2.08
TT vs. CT + CC 0.24 −0.34-1.32
TT vs. CC 0.06 −0.05-1.86
A1298C C vs. A 0.73 −1.60-2.25
CC + AC vs. AA 0.66 −2.03-1.31
CC vs. AC + AA 0.09 −0.17-2.39
CC vs. AA 0.14 −0.35-2.32
Major depression C677T T vs. C 0.18 −0.64-3.33
TT + CT vs. CC 0.35 −1.09-3.00
TT vs. CT + CC 0.40 −0.80-1.97
TT vs. CC 0.09 −0.21-2.52
A1298C C vs. A 0.03 −12.82–1.28
CC + AC vs. AA 0.08 −13.00-1.10
CC vs. AC + AA 0.05 −4.48-0.02
CC vs. AA 0.02 −4.78–0.81
Bipolar disorder C677T T vs. C 0.19 −1.45-6.66
TT + CT vs. CC 0.21 −1.62-6.66
TT vs. CT + CC 0.31 −0.95-2.81
TT vs. CC 0.18 −0.82-4.02
A1298C C vs. A 0.54 −30.72-19.79
CC + AC vs. AA 0.54 −17.02-10.90
CC vs. AC + AA 0.75 −24.98-31.11
CC vs. AA 0.82 −26.75-31.41

Funnel plots for assessing the publication bias risk in this meta-analysis. (A) Funnel plot for allele contrast (T vs. C) of C677T polymorphism in SZ. (B) Funnel plot for allele contrast (C vs. A) of A1298C polymorphism in SZ. (C) Funnel plot for allele contrast (T vs. C) of C677T polymorphism in MD. (D) Funnel plot for allele contrast (C vs. A) of A1298C polymorphism in MD. (E) Funnel plot for allele contrast (T vs. C) of C677T polymorphism in BPD. (F) Funnel plot for allele contrast (C vs. A) of A1298C polymorphism in BPD.

 Discussion

A mental disorder is a neurological disease with complicated etiology, which may be closely related to genetic factors. A great number of research on the susceptibility to mental illnesses (including SZ, MD, and BPD) have been undertaken using MTHFR gene polymorphism. Some studies supported the susceptibility variation of MTHFR in mental diseases (27, 31, 70, 96, 105, 69), whereas other studies showed a negative correlation (28, 29, 33, 46, 102, 46). These variations might be due to the type of disease, ethnicity, or sample size. Our meta-analysis incorporates all previous research and provides more reliable evidence for the association between mental illness and MTHFR SNPs.

For Sz, our meta-analysis found a substantial association between MTHFR C677T polymorphism and higher incidence of SZ, which is consistent with research by Hu et al. (22) and Peerbooms et al. (23). In addition, we found that MTHFR A1298C polymorphism was not correlated with increased SZ risk, which is consistent with Peerbooms et al. (23). However, Hu et al. (22) discovered a marginal correlation between the MTHFR A1298C polymorphism and SZ. The inconsistency may be mainly owing to the limited sample size in the previous meta-analyses. For MTHFR C677T and A1298C, the sensitivity analysis has no substantial change to the results. As a result, the study’s findings are relatively consistent.

For MD, our meta-analysis’s results showed a significant correlation between MTHFR C677T polymorphism and increased risk of MD. The meta-analysis of Wu et al. (107) supports our view, whereas Gaysina et al. (108) and Peerbooms et al. (23) discovered no association between the C677T and MD. These discrepancies might be due to ethnicity, sample size, and other factors. Sensitivity analysis showed no change in the overall correlation between C677T polymorphism and MD. Also, we found a correlation between the A1298C polymorphism and MD (in recessive models and homozygous models). However, after excluding two studies not in Hardy–Weinberg equilibrium (38, 95), we discovered that A1298C polymorphism was not correlated with depression. We suspect that the reason for this is the insufficient number of studies included.

For BPD, meta-analysis reveals that MTHFR C677T polymorphism is weakly related to the occurrence of diseases (in recessive models and homozygous models). The meta-analysis of Hu et al. (22) found a marginal connection of C677T with an elevated risk of BPD (the recessive model), but some studies (21, 109, 110) found no associations. Different numbers of studies included may cause the inconsistency. Our meta-analysis included all current research, providing more reliable evidence for the association between MTHFR C677T polymorphism and BPD. As for A1298C, we only found studies in Caucasian people, and we did not find any association in these studies. The sensitivity analysis has no change to the results. Therefore, the results of this study are generally robust.

Many researchers have discovered that MTHFR is closely related to cognitive function, such as verbal fluency, visual-motor coordination, attention selectivity, and distribution (111–113). MTHFR polymorphism may also cause central nerve injury and microvascular injury, affect the synthesis of central neurotransmitters and the methylation of central neural system amines and phospholipids, and eventually lead to various mental diseases (114). All these impairments are not specific to one disease; therefore, we guess MTHFR may work on the common pathogenesis of these psychiatric disorders.

Some limitations of this meta-analysis should be considered when interpreting the findings. Firstly, we can only search for English and Chinese articles with some language limitations. Second, publication bias cannot be ignored in the current study since Egger test findings are substantial in several SZ and MD genetic models. It may correlate to the editor’s decision for publication and so on. However, it is common that only the positive results are published, and negative findings are unavailable. And we could not exclude this kind of possibility. Furthermore, the number of articles on A1298C polymorphism with MD are insufficient to provide conclusive evidence. More original research is required to validate our results. Despite some limitations, our current research also has some value. First of all, our meta-analysis includes a large sample size, which can reduce errors. Secondly, we fully considered and analyzed the impact of race on the disease.

 Conclusion

Our meta-analysis findings demonstrate that MTHFR C677T polymorphism increases the risk of schizophrenia and severe depression in the general population, and a marginal correlation of MTHFR C677T with a higher risk of bipolar disorder has also been reported for the recessive model. More original research and a bigger sample size are required to validate our results. Nevertheless, the findings of our meta-analysis imply that MTHFR may play a significant role in the common pathogenesis of mental illness and that its variation may be involved in controlling the expression of genes associated with it. It would help in the early diagnosis and treatment of related mental disorders. Moreover, studies on risk factor analysis could be performed on psychiatric disorders to better prevent these mental health problems.

 Data availability statement

The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

 Author contributions

Y-XZ: conceptualization, software, data curation, and writing – original draft preparation. DH: conceptualization, methodology, and funding acquisition. L-PY: data curation and validation. CG: visualization and investigation. C-CC: software and validation. Z-YG: writing – reviewing and editing. H-MS: project administration and supervision. All authors contributed to the article and approved the submitted version.

 Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81803857) and Autonomous Subject of Beijing University of Chinese Medicine (Grant No. 2018-JYBZZ-XJSJJ002).

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.976428/full#supplementary-material

 References Barnett R. Depression. Lancet (London, England). (2019) 393:2113. 10.1016/s0140-6736(19)31151-1 Adorjan K Falkai P. Premature mortality, causes of death, and mental disorders. Lancet (London, England). (2019) 394:1784–6. 10.1016/s0140-6736(19)32521-8 Phillips ML Drevets WC Rauch SL Lane R. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry. (2003) 54:515–28. 10.1016/s0006-3223(03)00171-9 Malhi GS Mann JJ. Depression. Lancet (London, England). (2018) 392:2299–312. 10.1016/s0140-6736(18)31948-2 Owen MJ Sawa A Mortensen PB. Schizophrenia. Lancet (London, England). (2016) 388:86–97. 10.1016/s0140-6736(15)01121-6 Dennison CA Legge SE Pardinas AF Walters JTR. Genome-wide association studies in schizophrenia: Recent advances, challenges, and future perspective. Schizophr Res. (2019) 217:4–12. 10.1016/j.schres.2019.10.048 31780348 Schwab SG Wildenauer DB. Genetics of psychiatric disorders in the GWAS era: An update on schizophrenia. Eur Arch Psychiatry Clin Neurosci. (2013) 263(Suppl. 2):S147–54. 10.1007/s00406-013-0450-z 24071914 Bagley PJ Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci U S A. (1998) 95:13217–20. 10.1073/pnas.95.22.13217 9789068 Födinger M Hörl WH Sunder-Plassmann G. Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol. (2000) 13:20–33. Wan L Li Y Zhang Z Sun Z He Y Li R. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry. (2018) 8:242. 10.1038/s41398-018-0276-6 30397195 Frosst P Blom HJ Milos R Goyette P Sheppard CA Matthews RG A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet. (1995) 10:111–3. 10.1038/ng0595-111 7647779 Lewis SJ Lawlor DA Smith GD Araya R Timpson N Day INM The thermolabile variant of Mthfr is associated with depression in the British Women’s heart and health study and a meta-analysis. Mol Psychiatry. (2006) 11:352–60. 10.1038/sj.mp4001790 Lewis SJ Zammit S Gunnell D Smith GD. A meta-analysis of the MTHFR C677t polymorphism and schizophrenia risk. Am J Med Genet Part B, Neuropsychiatric Genet Off Publ Int Soc Psychiatric Genet. (2005) 135b:2–4. 10.1002/ajmg.b.30170 15729744 van der Put NM Gabreëls F Stevens EM Smeitink JA Trijbels FJ Eskes TK A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am J Hum Genet. (1998) 62:1044–51. 10.1086/301825 9545395 Liew SC Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677t polymorphism: Epidemiology, metabolism and the associated diseases. Eur J Med Genet. (2015) 58:1–10. 10.1016/j.ejmg.2014.10.004 25449138 Goyette P Pai A Milos R Frosst P Tran P Chen Z Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome Off J Int Mamm Genome Soc. (1998) 9:652–6. 10.1007/s003359900838 9680386 Krebs MO Bellon A Mainguy G Jay TM Frieling H. One-carbon metabolism and schizophrenia: Current challenges and future directions. Trends Mol Med. (2009) 15:562–70. 10.1016/j.molmed.2009.10.001 19896901 Dror DK Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: Current knowledge and possible mechanisms. Nutr Rev. (2008) 66:250–5. 10.1111/j.1753-4887.2008.00031.x 18454811 Harrison PJ Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Mol Psychiatry. (2005) 10:40–68; image 5. 10.1038/sj.mp.4001558 15263907 Sun D Stuart GW Jenkinson M Wood SJ McGorry PD Velakoulis D Brain surface contraction mapped in first-episode schizophrenia: A longitudinal magnetic resonance imaging study. Mol Psychiatry. (2009) 14:976–86. 10.1038/mp.2008.34 18607377 Cohen-Woods S Craig I Gaysina D Gray J Gunasinghe C Craddock N The bipolar association case-control study (BACCS) and meta-analysis: No association with the 5,10-methylenetetrahydrofolate reductase gene and bipolar disorder. Am J Med Genet Part B Neuropsychiatric Genet Off Publ Int Soc Psychiatric Genet. (2010) 153b:1298–304. 10.1002/ajmg.b.31101 20552676 Hu CY Qian ZZ Gong FF Lu SS Feng F Wu YL Methylenetetrahydrofolate reductase (MTHFR) polymorphism susceptibility to schizophrenia and bipolar disorder: An updated meta-analysis. J Neural Transmission (Vienna, Austria 1996). (2015) 122:307–20. 10.1007/s00702-014-1261-8 24938371 Peerbooms OL van Os J Drukker M Kenis G Hoogveld L MTHFR in Psychiatry Group Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: Evidence for a common genetic vulnerability? Brain Behav Immun. (2011) 25:1530–43. 10.1016/j.bbi.2010.12.006 21185933 Melsen WG Bootsma MC Rovers MM Bonten MJ. The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. (2014) 20:123–9. 10.1111/1469-0691.12494 24320992 DerSimonian R Laird N. Meta-analysis in clinical trials revisited. Contemporary Clin Trials. (2015) 45(Pt A):139–45. 10.1016/j.cct.2015.09.002 26343745 Egger M Davey Smith G Schneider M Minder C. Bias in meta-analysis detected by a simple, Graphical Test. BMJ (Clin Res Ed). (1997) 315:629–34. 10.1136/bmj.315.7109.629 9310563 Arinami T Yamada N Yamakawa-Kobayashi K Hamaguchi H Toru M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. (1997) 74:526–8. 10.1002/(sici)1096-8628(19970919)74:53.0.co;2-e Kunugi H Fukuda R Hattori M Kato T Tatsumi M Sakai T C677t polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry. (1998) 3:435–7. 10.1038/sj.mp.4000390 9774778 Virgos C Martorell L Simó JM Valero J Figuera L Joven J Plasma homocysteine and the methylenetetrahydrofolate reductase C677t gene variant: Lack of association with schizophrenia. Neuroreport. (1999) 10:2035–8. 10.1097/00001756-199907130-00008 10424670 Joober R Benkelfat C Lal S Bloom D Labelle A Lalonde P Association between the Methylenetetrahydrofolate reductase 677c–>T missense mutation and schizophrenia. Mol Psychiatry. (2000) 5:323–6. 10.1038/sj.mp.4000724 10889537 Sazci A Ergül E Güzelhan Y Kaya G Kara I. Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Brain Res Mol Brain Res. (2003) 117:104–7. 10.1016/s0169-328x(03)00327-9 Tan EC Chong SA Lim LC Chan AO Teo YY Tan CH Genetic analysis of the thermolabilemethylenetetrahydrofolate reductase variant in schizophrenia and mood disorders. Psychiatric Genet. (2004) 14:227–31. 10.1097/00041444-200412000-00012 15564899 Yu L Li T Robertson Z Dean J Gu NF Feng GY No association between polymorphisms of methylenetetrahydrofolate reductase gene and schizophrenia in both chinese and scottish populations. Mol Psychiatry. (2004) 9:1063–5. 10.1038/sj.mp.4001566 15289817 Sazci A Ergul E Kucukali I Kara I Kaya G. Association of the C677t and A1298c polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: Association is significant in men but not in women. Progr Neuro Psychopharmacol Biol Psychiatry. (2005) 29:1113–23. 10.1016/j.pnpbp.2005.06.022 16084002 Vilella E Virgos C Murphy M Martorell L Valero J Simó JM Further evidence that hyperhomocysteinemia and methylenetetrahydrofolate reductase C677t and A1289c polymorphisms are not risk factors for schizophrenia. Progr Neuro Psychopharmacol Biol Psychiatry. (2005) 29:1169–74. 10.1016/j.pnpbp.2005.07.001 16076517 Kempisty B Mostowska A Gorska I Luczak M Czerski P Szczepankiewicz A Association of 677c>T polymorphism of methylenetetrahydrofolate reductase (Mthfr) gene with bipolar disorder and schizophrenia. Neurosci Lett. (2006) 400:267–71. 10.1016/j.neulet.2006.02.055 16545905 Philibert R Gunter T Hollenbeck N Adams WJ Bohle P Packer H No association of the C677t methylenetetrahydrofolate reductase polymorphism with schizophrenia. Psychiatric Genet. (2006) 16:221–3. 10.1097/01.ypg.0000242192.28526.fa Lee YS Han DH Jeon CM Lyoo IK Na C Chae SL Serum Homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients. Neuroreport. (2006) 17:743–6. 10.1097/01.wnr.0000215777.99473.52 Yang D-Y Lu X-B Li Y-H Tong Z-S Fu Y Yang M-X The association of methylenetetrahydrofolate reductase gene polymorphism, plasma homocysteine level and first-episode schizophrenia [in Chinese]. Chin Hehavioral Med Sci. (2007) 16:901–2. 10.3760/cma.j.issn.1674-6554.2007.10.013 30704229 Jonsson EG Larsson K Vares M Hansen T Wang AG Djurovic S Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: An association study. Am J Med Genet Part B Neuropsychiatric Genet Off Publ Int Soc Psychiatric Genet. (2008) 147B:976–82. 10.1002/ajmg.b.30671 18165967 Muntjewerff J-W. Meta-analysis of plasma homocysteine and methylenetetrahydrofolate reductase (MTHFR) polymorphisms in schizophrenia. Biol Psychiatry. (2008) 63:134S–S. Roffman JL Gollub RL Calhoun VD Wassink TH Weiss AP Ho BC MTHFR 677c –> T genotype disrupts prefrontal function in schizophrenia through an interaction with Comt 158val –> Met. Proc Natl Acad Sci U S A. (2008) 105:17573–8. 10.1073/pnas.0803727105 18988738 Feng LG Song ZW Xin F Hu J. Association of plasma homocysteine and methylenetetrahydrofolate reductase C677t gene variant with schizophrenia: A chinese han population-based case-control study. Psychiatry Res. (2009) 168:205–8. 10.1016/j.psychres.2008.05.009 19564051 Betcheva ET Mushiroda T Takahashi A Kubo M Karachanak SK Zaharieva IT Case-control association study of 59 candidate genes reveals the DRD2 SNP Rs6277 (C957t) as the only susceptibility factor for schizophrenia in the bulgarian population. J Hum Genet. (2009) 54:98–107. 10.1038/jhg.2008.14 19158809 García-Miss MR Pérez-Mutul J López-Canul B Solís-Rodríguez F Puga-Machado L Oxté-Cabrera A Folate, homocysteine, interleukin-6, and tumor necrosis factor alfa levels, but not the methylenetetrahydrofolate reductase C677t polymorphism, are risk factors for schizophrenia. J Psychiatric Res. (2010) 44:441–6. 10.1016/j.jpsychires.2009.10.011 19939410 Kang HJ Choe BM Kim SH Son SR Lee KM Kim BG No association between functional polymorphisms in COMT and MTHFR and schizophrenia risk in Korean population. Epidemiol Health. (2010) 32:e2010011. 10.4178/epih/e2010011 21217836 Ye X Zhang X Wang H. Study association of MTHFR C677t polymorphism and schizophrenia [in Chinese]. Heilongjiang Med J. (2010) 34:641–5. Bouaziz N Ayedi I Sidhom O Kallel A Rafrafi R Jomaa R Plasma homocysteine in schizophrenia: Determinants and clinical correlations in tunisian patients free from antipsychotics. Psychiatry Res. (2010) 179:24–9. 10.1016/j.psychres.2010.04.008 20471108 Arzaghi SM Hossein-Nezhad A Shariat SV Ghodsipour A Shams J Larijani B. C677t methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in schizophrenia and bipolar disorder: An association study in Iranian population. Iranian J Psychiatry. (2011) 6:1–6. 22952513 Kim SG Song JY Joo EJ Jeong SH Kim SH Lee KY No Association of functional polymorphisms in methlylenetetrahydrofolate reductase and the risk and minor physical anomalies of schizophrenia in Korean population. J Korean Med Sci. (2011) 26:1356–63. 10.3346/jkms.2011.26.10.1356 22022190 Muntjewerff JW Ophoff RA Buizer-Voskamp JE Strengman E den Heijer M Consortium G. Effects of season of birth and a common MTHFR gene variant on the risk of schizophrenia. Eur Neuropsychopharmacol J Eur College Neuropsychopharmacol. (2011) 21:300–5. 10.1016/j.euroneuro.2010.10.001 21093223 Tsutsumi A Glatt SJ Kanazawa T Kawashige S Uenishi H Hokyo A The genetic validation of heterogeneity in schizophrenia. Behav Brain Funct BBF. (2011) 7:43. 10.1186/1744-9081-7-43 21981786 Zhang X Liu T Yang Y Deng X Yan X Yang K Association analysis of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and treatment-resistant schizophrenia [in Chinese]. J Clin Psychiatry. (2012) 22:293–7. Lochman J Plesník J Janout V Povová J Míšek I Dvořáková D Interactive effect of MTHFR and Adra2a gene polymorphisms on pathogenesis of schizophrenia. Neuro Endocrinol Lett. (2013) 34:792–7. 24522021 Zhang Y Yan H Tian L Wang F Lu T Wang L Association of MTHFR C677t polymorphism with schizophrenia and its effect on episodic memory and gray matter density in patients. Behav Brain Res. (2013) 243:146–52. 10.1016/j.bbr.2012.12.061 23318463 Kontis D Theochari E Fryssira H Kleisas S Sofocleous C Andreopoulou A Comt and MTHFR polymorphisms interaction on cognition in schizophrenia: An exploratory study. Neurosci Lett. (2013) 537:17–22. 10.1016/j.neulet.2013.01.012 23353103 El-Hadidy MA Abdeen HM Abd El-Aziz SM Al-Harrass M. MTHFR gene polymorphism and age of onset of schizophrenia and bipolar disorder. BioMed Res Int. (2014) 2014:318483. 10.1155/2014/318483 25101272 Hei G Pang L Chen X Zhang W Zhu Q Lü L [Association of serum folic acid and homocysteine levels and 5, 10-methylenetetrahydrofolate reductase gene polymorphism with schizophrenia]. Zhonghuayixuezazhi. (2014) 94:2897–901. 25549641 Nishi A Numata S Tajima A Kinoshita M Kikuchi K Shimodera S Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677t polymorphism in schizophrenia. Schizophrenia Bull. (2014) 40:1154–63. 10.1093/schbul/sbt154 24535549 Foroughmand AM Galehdari H Pooryasin A Ajam T Kazemi-Nezhad SR. Additive effect of MTHFR and GRIN1 genetic polymorphisms on the risk of schizophrenia. Mol Biol Res Commun. (2015) 4:33–42. 27843994 Misiak B Laczmanski L Sloka NK Szmida E Piotrowski P Loska O Metabolic dysregulation in first-episode schizophrenia patients with respect to genetic variation in one-carbon metabolism. Psychiatry Res. (2016) 238:60–7. 10.1016/j.psychres.2016.01.077 27086212 Takano Y Ozeki Y Sekine M Fujii K Watanabe T Okayasu H Multi-regression analysis revealed a relationship between l-serine and methionine, a component of one-carbon metabolism, in the normal control but not in the schizophrenia. Ann Gen Psychiatry. (2016) 15:23. 10.1186/s12991-016-0113-3 27588034 Wang W-P Fan W Shi B Tong C Wang X Cai J Effect of MTHFR gene on the schizophrenia and its cognitive function [in Chinese]. Chin J Med Genet. (2017) 34:905–8. Oniki K Ishioka M Osaki N Sakamoto Y Yoshimori Y Tomita T Association between oxidative stress-related genes polymorphisms and metabolic abnormalities among schizophrenia patients. Clin Neuropsychopharmacol Ther. (2017) 8:25–37. 10.5234/cnpt.8.25 Debost JC Debost M Grove J Mors O Hougaard DM Borglum AD Comt Val158met and MTHFR C677t moderate risk of schizophrenia in response to childhood adversity. ActapsychiatricaScandinavica. (2017) 136:85–95. 10.1111/acps.12761 28556887 Zhilyaeva TV Sergeeva AV Blagonravova AS Kasimova LN Kuznetsov KV Golovanova VI Association study of methylenetetrahydrofolate reductase genetic polymorphism 677c>T with schizophrenia in hospitalized patients in population of European Russia. Asian J Psychiatry. (2018) 32:29–33. 10.1016/j.ajp.2017.11.027 29202425 Ota M Sato N Yoshida F Hattori K Hidese S Teraishi T A polymorphism of the methylenetetrahydrofolate reductase gene confers susceptibility to schizophrenia and related brain changes. Schizophr Res. (2019) 208:462–4. 10.1016/j.schres.2019.03.002 30852115 Wan L Li Y Zhou Y Li R Zheng Y. Age matters: An atypical association between polymorphism of MTHFR and clinical phenotypes in children with schizophrenia. J Mol Neurosci MN. (2019) 69:485–93. 10.1007/s12031-019-01382-0 31302825 Wan L Zhang G Liu M Wang C Li Y Li R. Sex-specific effects of methylenetetrahydrofolate reductase polymorphisms on schizophrenia with methylation changes. Compr Psychiatry. (2019) 94:152121. 10.1016/j.comppsych.2019.152121 31476590 Kelly CB McDonnell AP Johnston TG Mulholland C Cooper SJ McMaster D The MTHFR C677t polymorphism is associated with depressive episodes in patients from northern Ireland. J Psychopharmacol (Oxford, England). (2004) 18:567–71. 10.1177/0269881104047285 15582924 Reif A Pfuhlmann B Lesch KP. Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Progr Neuro Psychopharmacol Biol Psychiatry. (2005) 29:1162–8. 10.1016/j.pnpbp.2005.06.027 16055253 Yuan Y-G Li H Wu R. The association of plasma homocysteine level, methylene tetrahydrofolate reductase gene polymorphism and depression in the elderly [in Chinese]. Chin J Psychiatry. (2005) 38:150. Cheng-Sheng C Tsai J-C Hin-Yeung T Yu-Ting K. Homocysteine levels, MTHFR C677t genotype, and mrihyperintensities in late-onset major depressive disorder. Am J Geriatric Psychiatry. (2005) 13:869–75. 10.1176/appi.ajgp.13.10.869 16223965 Yuan YG. Plasma homocysteine levels and MTHFR polymorphisms in senile depression and mild Alzheimer’s disease [in Chinese]. Chin J Geriatr. (2007) 26:767–69. Slopien R Jasniewicz K Meczekalski B Warenik-Szymankiewicz A Lianeri M Jagodzinski PP. Polymorphic variants of genes encoding MTHFR, MTR, and MTHFD1 and the risk of depression in postmenopausal women in Poland. Maturitas. (2008) 61:252–5. 10.1016/j.maturitas.2008.08.002 18801628 Zhao G-Q. Association of polymorphism of homocysteine and MTHFR gene C677t with major depression [in Chinese]. Chin J Nerv Ment Dis. (2008) 34:378–80. Yuan YG Zhang ZJ Li JJ. Plasma homocysteine but not MTHFR gene polymorphism is associated with geriatric depression in the Chinese Population. Actaneuropsychiatrica. (2008) 20:251–5. 10.1111/j.1601-5215.2008.00290.x 25384376 Hong ED Taylor WD McQuoid DR Potter GG Payne ME Ashley-Koch A Influence of the MTHFR C677t polymorphism on magnetic resonance imaging hyperintensity volume and cognition in geriatric depression. Am J Geriatric Psychiatry Off J Am Assoc Geriatric Psychiatry. (2009) 17:847–55. 10.1097/JGP.0b013e3181aad5b2 19910873 Kim JM Stewart R Kim SW Yang SJ Shin IS Yoon JS. Modification by two genes of associations between general somatic health and incident depressive syndrome in older people. Psychosomatic Med. (2009) 71:286–91. 10.1097/PSY.0b013e3181990fff 19251870 Pan CC McQuoid DR Taylor WD Payne ME Ashley-Koch A Steffens DC. Association analysis of the COMT/MTHFR genes and geriatric depression: An MRI study of the putamen. Int J Geriatric Psychiatry. (2009) 24:847–55. 10.1002/gps.2206 19235787 Cao L Liu Z Zhao L. Correlation analysis of plasma homocysteine and MTHFR gene polymorphism with post-stroke depression [in Chinese]. Guangdong Med J. (2010) 31:2946–9. Zeman M Jachymova M Jirak R Vecka M Tvrzicka E Stankova B Polymorphisms of genes for brain-derived neurotrophic factor, methylenetetrahydrofolate reductase, tyrosine hydroxylase, and endothelial nitric oxide synthase in depression and metabolic syndrome. Folia Biol. (2010) 56:19–26. 20163778 Feng L-G Shao C Liu Y Tao Y Hao X. The detection of genepolymorphisms of MTHFR C677t and A1298c in severe depression patients [in Chinese]. Basic Clin Med. (2010) 30:811–4. Li ZZ Yu SY Zhang C Yuan CM Hong W Wang Y Association of MTHFR gene C677t polymorphisms and depression in han populations. J Shanghai Jiaotong Univ (Med Sci). (2010) 30:624–7. Song Z-W. Association of Methylenetetrahydrofolate reductase gene polymorphism and plasma homocysteine with major depression [in Chinese]. J Med Postgraduates. (2010) 23:934–7. Lizer MH Bogdan RL Kidd RS. Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677t polymorphism in depressed versus nondepressed patients. J Psychiatric Pract. (2011) 17:404–9. 10.1097/01.pra.0000407963.26981.a6 Zhao H-F Qiao J Zhu X-H. The association study of MTHFR gene polymorphism with depression [in Chinese]. J Psychiatry. (2011) 24:435–7. 10.3969/j.issn.1009-7201.2011.06.011 Chojnicka I Sobczyk-Kopciol A Fudalej M Fudalej S Wojnar M Waskiewicz A No association between MTHFR C677t polymorphism and completed suicide. Gene. (2012) 511:118–21. 10.1016/j.gene.2012.09.019 22982411 Evinova A Babusikova E Straka S Ondrejka I Lehotsky J. Analysis of genetic polymorphisms of brain-derived neurotrophic factor and methylenetetrahydrofolate reductase in depressed patients in a slovak (Caucasian) population. Gen Physiol Biophys. (2012) 31:415–22. 10.4149/gpb_2012_049 24503400 Qiao J Zhao H-F Zhu X-H Geng D-Q. The study of MTHFR Gene Polymorphism in Depression [in Chinese]. J Clin Psychiatry. (2012) 22:92–4. Shen X Wu Y Guan T Wang X Qian M Lin M Association analysis of COMT/MTHFR polymorphisms and major depressive disorder in Chinese Han population. J Affect Disord. (2014) 161:73–8. 10.1016/j.jad.2014.03.008 24751310 Sayadi MA Achour O Ezzaher A Hellara I Omezzine A Douki W Ct Genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677t polymorphism is protector factor of major depressive disorder in the Tunisian Population: A case control study. Ann Gen Psychiatry. (2016) 15:18. 10.1186/s12991-016-0103-5 27478487 Mei F Wu Y Ding G. Association analysis of the MTHFR polymorphism and post-stroke depression in the elderly [in Chinese]. Geriatrics Health Care. (2016) 22:363–5+9. 30174331 Huang Z-H Zhou H-Y Iv W-C Cheng X-Y Chen F. The correlation between MTHFR gene, Erαgene Polymorphism and Postpartum Depression Susceptibility [in Chinese]. J Med Theory Pract. (2017) 30:1108–9+22. Li Y Yue H Li H. Effect of folic acid intake during pregnancy and MTHFR polymorphism on postpartum depression [in Chinese]. Chin J Woman Child Health Res. (2017) 28:632–5. 10.1038/ejcn.2011.136 21772318 Mei F Wu Y Ding G Pan F Chen L Wu J. Association of methylenetetrahydrofolate reductase Gene 677c>T polymorphism with post-stroke depression risk and antidepressant treatment response in Han Chinese. JPMA J Pakistan Med Assoc. (2018) 68:888–92. 30174331 Saraswathy KN Ansari SN Kaur G Joshi PC Chandel S. Association of vitamin B12 mediated hyperhomocysteinemia with depression and anxiety disorder: A cross-sectional study among bhil indigenous population of India. ClinNutr ESPEN. (2019) 30:199–203. 10.1016/j.clnesp.2019.01.009 30904222 Zhao G-Q Jiao Z-A Wang S-M Liu Z-X Shi H. An association analysis of methylenetetrahydrofolate dehydrogenase polymorphism, plasma homocysteine levels and bipolar affective disorder [in Chinese]. J Psychiatry. (2008) 21:130–2. Ozbek Z Kucukali CI Ozkok E Orhan N Aydin M Kilic G Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives. Progr Neuro Psychopharmacol Biol Psychiatry. (2008) 32:1331–7. 10.1016/j.pnpbp.2008.04.016 18513846 Chen Z Liu Y Zhang D Liu Z Wang P Zhou D C677t methylenetetrahydrofolate reductase gene polymorphisms in bipolar disorder: An association study in the Chinese population and a meta-analysis of genetic association studies. Neurosci Lett. (2009) 449:48–51. 10.1016/j.neulet.2008.10.077 18983889 Ezzaher A Mouhamed DH Mechri A Omezzine A Neffati F Douki W Hyperhomocysteinemia in Tunisian Bipolar I patients. Psychiatry Clin Neurosci. (2011) 65:664–71. 10.1111/j.1440-1819.2011.02284.x 22176285 Permoda-Osip A Dmitrzak-Weglarz M Hauser J Rybakowski JK. Are genes connected with homocysteine metabolism associated with bipolar disorder? Neuropsychobiology. (2014) 69:107–11. 10.1159/000358091 24577139 Wang LJ Lee SY Chen SL Chang YH Chen PS Huang SY A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with Bipolar II disorder. Sci Rep. (2015) 5:8813. 10.1038/srep08813 25744938 Rahimi Z Kakabaraee K Garavand A Rahimi Z. The T allele of MTHFR C.C677t and Its synergism with G (Val 158) allele of COMT C.G472a polymorphism are associated with the risk of Bipolar I disorder. Genet Test Mol Biomarkers. (2016) 20:510–5. 10.1089/gtmb.2016.0061 27447284 Kempisty B Bober A Luczak M Czerski P Szczepankiewicz A Hauser J Distribution of 1298a>C polymorphism of methylenetetrahydrofolate reductase gene in patients with bipolar disorder and schizophrenia. Eur Psychiatry J Assoc Eur Psychiatrists. (2007) 22:39–43. 10.1016/j.eurpsy.2006.11.003 17188847 Zhang C Xie B Du Y Cheng W Fang Y Yu S. Further evidence that methylenetetrahydrofolate reductase A1298c polymorphism is a risk factor for schizophrenia. J Neural Transm (Vienna). (2010) 117:1115–7. 10.1007/s00702-010-0442-3 20694488 Wu YL Ding XX Sun YH Yang HY Chen J Zhao X Association between MTHFR C677t polymorphism and depression: An updated meta-analysis of 26 Studies. Progr Neuro-Psychopharmacol Biol Psychiatry. (2013) 46:78–85. 10.1016/j.pnpbp.2013.06.015 23831680 Gaysina D Cohen S Craddock N Farmer A Hoda F Korszun A No Association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: Results of the Depression Case Control (DECC) study and a meta-analysis. Am J Med Genet Part B Neuropsychiatric Genet Off Publ Int Soc Psychiatric Genet. (2008) 147B:699–706. 10.1002/ajmg.b.30665 18165972 Rai V. Evaluation of methylenetetrahydrofolate reductase gene variant (C677t) as risk factor for bipolar disorder. Cell Mol Biol (Noisy-le-Grand, France). (2011) 57:OL1558–66. 21955385 Zintzaras E. C677t and A1298c methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: A meta-analysis of genetic association studies. Psychiatric Genet. (2006) 16:105–15. 10.1097/01.ypg.0000199444.77291.e2 Roffman JL Weiss AP Deckersbach T Freudenreich O Henderson DC Purcell S Effects of the methylenetetrahydrofolate reductase (MTHFR) C677t polymorphism on executive function in schizophrenia. Schizophr Res. (2007) 92:181–8. 10.1016/j.schres.2007.01.003 17344026 Wang X Wang Z Wu Y Yuan Y Hou Z Hou G. Association analysis of the Catechol-O-Methyltransferase/methylenetetrahydrofolate reductase genes and cognition in late-onset depression. Psychiatry Clin Neurosci. (2014) 68:344–52. 10.1111/pcn.12133 24373005 Zhilyaeva TV Sergeyeva AV Kasimova LN Blagonravova AS. Cognitive function dynamics during folate augmented therapy in patients with schizophrenia carrying MTHFR677c>T gene polymorphism: A pilot study. Sovremennyetehnologii Med. (2015) 7:147–53. 10.17691/stm2015.7.4.20 Liu WW Dong XZ Liu P. Mthfr 677c/T polymorphism-new ideas about depressive disorder treatment. Chin Pharmacol Bull. (2015) 31:915–9. 10.3969/j.issn.1001-1978.2015.07.006