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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
© The Author(s) 2016
Received: 4 February 2016
Accepted: 29 June 2016
Published: 30 July 2016
Major depressive disorder (MDD) is a common psychiatric disorder with considerable mortality. Death from unnatural causes, largely suicidal or quasi-suicidal, has a particularly high risk for the functional disorders, especially depression and schizophrenia. One of the prospective risk factors for this disease is hyperhomocysteinemia and folate deficiency. The methylenetetrahydrofolate reductase (MTHFR) gene encodes for a 5-methylenetetrahydrofolate reductase involved in folate metabolism and neurotransmitter synthesis. The aim of this research is to study the association between the C677T polymorphism of MTHFR gene and depression in Tunisian population, to explore their relationship with clinical and therapeutic characteristics of this disease. And it may lead to discover a novel marker to identify a patient with a higher risk of development of depressive disorder to be. This marker can be used for better therapeutic management and prevent disease installation.
Our study included 208 depressive patients, 187 controls aged between 44.1 ± 13.5 and 38.9 ± 13.2 years, respectively. MTHFR gene polymorphisms were determined by PCR–RFLP (polymerase chain reaction–restriction fragment length polymorphism).
No significant difference was detected in the distribution of the genotype frequencies of MTHFR C677T polymorphisms (χ 2 = 5.443, df = 2, p = 0.066) between patients and controls. But when we study the risk of these genotypes, CT genotype is significantly more frequent in controls compared to patients, it may be a protection from depression (OR = 0.655, CI 95 % = 0.432–0.995, p = 0.047, OR* = 0.638, CI 95 %* = 0.415–0.983, p* = 0.04, before and after adjustment). Women, TT Genotype can increase four times the risk to be depressive. Addictive behavior seems to be associated with CT genotype and there was no significant association between clinical and therapeutic characteristics and this polymorphism.
This paper is the first study to prove that CT genotype of MTHFR C677T polymorphism may protect from depression and TT genotype seems to be associated with women’s depression. Further studies are required with other polymorphisms and biochemical factors that must be investigated to clarify the implication of MTHFR C677T polymorphism in the pathophysiology of depression.
Major depressive disorder (MDD) is a common psychiatric disorder with considerable mortality  which affects 121 million people worldwide . The prevalence of depression in Tunisia is over 7 % . Death from unnatural causes, largely suicidal or quasi-suicidal, has a particularly, high risk for substance abuse and eating disorders and a high risk for the functional disorders, especially MDD and schizophrenia . The etiology of this MDD remains unclear, both gene–gene and gene-environment interactions are believed to have an important role on the development of this disease .
The genetic of depression has been extensively investigated, López-León et al.  has listed more than 393 polymorphisms in 102 genes, who were tested to have a possible relationship with depression. One promising candidate genetic marker for depression prognosis is the methylenetetrahydrofolate reductase (MTHFR) gene. This gene encodes for a 5-methylenetetrahydrofolate reductase involved in folate metabolism and neurotransmitter synthesis. Folate, vitamin B6 and vitamin B12 are used as cofactors in the metabolisation of homocysteine. Hyperhomocysteinemia and folate deficiency are prospective risk factors for depression [6–9]. Homocysteine or its metabolites may have an excitotoxic effect on neurons and may inhibit methylation processes in the central nervous system, it is toxic to the neurons, endothelial cells, can induce DNA strand breakage, oxidative stress, and apoptosis [10, 11]. This reduction of the MTHFR enzyme activity and the mild elevation of homocysteine plasma are probably caused by the C-T substitution at the 677 nucleotide in the MTHFR gene and it seems to be the major genetic cause . Studies are focused on this hypothesis but controversial results are found in the case–control studies investigating the association between the MTHFR C677T polymorphism and depression. Gilbody et al.  and Wu et al. , in their meta-analysis have found a positive association with MTHFR C766T polymorphism and the risk of depression, but Zintzaras  and Gaysina et al.  reports the absence of association in their meta-analysis. These controversial results may be explained by the size of population and the ethnic and geographic variation between populations.
In our case, we searched to study the relationship of this polymorphism with depression and different characteristics (socio-demographic, clinical and therapeutics) in Tunisian population of center. And this may lead to discover a novel marker to identify a patient with a higher risk of development of depressive disorder. This genetic marker can be used for better therapeutic management and prevent disease installation through treatment, psychological support and nutrition. A detection particular combination of polymorphism of different genes may confer a better exploration of earlier onset or presence of the different forms of pathology.
Patients and methods
The study was conducted in the Department of Psychiatry, of the University Hospital of Monastir, Tunisia, included 208 depressive patients and 187 controls without psychiatric or somatic pathology. The mean age of the 208 patients, including 91 males and 117 females, was 44.11 ± 13.52 years, while the mean age of the 187 controls including 91 males and 95 females, was 38.53 ± 13.22 years.
Demographic and clinical data of the study population
Gender: male/female (ratio)
44.11 ± 13.518
38.53 ± 13.222
Youth (<20 years)
11 (5.3 %)
17 (9 %)
Adult (20 ≤ years < 50)
122 (58.6 %)
125 (66.9 %)
Old (≤50 years)
75 (36.1 %)
45 (24.1 %)
27.098 ± 5.60
26.962 ± 4.58
72 (34.6 %)
71 (38 %)
75 (36.1 %)
73 (39 %)
61 (29.3 %)
43 (23 %)
64 (32 %)
59 (32 %)
136 (68 %)
128 (68 %)
42 (20.2 %)
40 (21.4 %)
164 (78.8 %)
17 (8.2 %)
8 (4.3 %)
191 (91.8 %)
179 (95.7 %)
Tricyclic antidepressants (TCA)
SIRS + TCA
Genomic DNA was extracted and isolated from EDTA blood samples by salting-out method . The MTHFR C677T polymorphisms of the 5,10-methylenetetrahydrofolate reductase gene has been studied by the protocol described previously by Frost et al. . In brief, a polymerase chain reaction (PCR) method using specific primers was carried out and the PCR products were digested with HinfI and then electrophoresed on 3 % agarose gels stained with ethidium bromide and UV transillumination. The uncut amplicon is 198 base pairs (bp) length. After digestion, the “T” allele gives 173 and 25 bp fragments, and the “C” allele gives one fragment with 198 bp fragments.
We have performed a case–control study on depressive and safe Tunisian population. Statistical analyses were performed using SPSS 17.0 (SPSS, Chicago, IL, USA). Hardy–Weinberg equilibrium was evaluated and genotype frequencies were compared by Chi-squared test (χ 2). Quantitative variables were presented as mean ± SD and comparisons were performed using the Student’s t test. Qualitative variable comparisons were performed using the χ 2 test. Odd ratios (ORs) and their 95 % confidence interval (CI) were calculated. The differences in demographic, clinical and therapeutic characteristics of patients were assessed among the MTHFR genotype using analysis of variance (ANOVA). Adjustment for potential confounder factors (age, drugs consumption) was performed by binary logistic regression. The statistical significance level was set at p ≤ 0.05.
Genotype frequencies of the C677T polymorphisms in the gene in patients and in controls
χ 2, df, p
105 (51 %)
80 (43 %)
χ 2 = 5.443/ddl = 2//p = 0.066
80 (38 %)
93 (50 %)
23 (11 %)
14 (7 %)
Association between depression and MTHFR C766T polymorphisms
IC 95 %
IC 95 % adjusted
Genotype frequencies of the C677T polymorphisms in the gene in men patients and in men controls
χ 2 = 0.810/ddl = 2//p = 0.667
Association between depression and MTHFR C766T polymorphisms in men
IC 95 %
IC 95 % adjusted
Genotype frequencies of the C677T polymorphisms in the gene in women patients and in women controls
χ 2 = 8.921/ddl = 2//p = 0.012
Association between depression and MTHFR C766T polymorphism in women
IC 95 %
IC 95 % adjusted
Demographic, clinical and therapeutic characteristics of Depressives patients according to the MTHFR C766T genotypes
45.37 ± 13.036
42.16 ± 14.132
45.09 ± 13.287
27.127 ± 5.992
26.8113 ± 5.992
27.965 ± 5.201
43 (47.2 %)
37 (40.7 %)
11 (12.1 %)
62 (53 %)
43 (36.8 %)
12 (10.2 %)
12 (28.6 %)
26 (61.9 %)
4 (9.5 %)
52 (31.7 %)
93 (56.7 %)
5 (29.4 %)
12 (70.6 %)
100 (52.4 %)
68 (35.6 %)
23 (12 %)
28 (41.2 %)
34 (50 %)
6 (8.8 %)
77 (55 %)
46 (32.9 %)
17 (12.1 %)
9 (32.1 %)
14 (50 %)
5 (17.9 %)
96 (53.3 %)
18 (10 %)
19 (45.2 %)
16 (38.1 %)
7 (16.7 %)
71 (51.1 %)
55 (39.6 %)
13 (9.3 %)
15 (55.6 %)
9 (33.3 %)
3 (11.1 %)
12 (36.4 %)
14 (42.4 %)
7 (21.2 %)
75 (55.1 %)
52 (38.2 %)
9 (6.7 %)
18 (46.2 %)
14 (35.9 %)
7 (17.9 %)
Type of anxiety
23 (67.7 %)
1 (2.9 %)
37 (48.1 %)
30 (38.9 %)
10 (13 %)
4 (100 %)
Panic and general anxiety
1 (100 %)
39 (50 %)
32 (41.1 %)
7 (8.9 %)
66 (50.8 %)
48 (36.9 %)
16 (12.3 %)
1 (25 %)
2 (50 %)
1 (25 %)
18 (48.7 %)
15 (40.5 %)
4 (10.8 %)
10 (55.6 %)
2 (11.1 %)
27 (54 %)
19 (38 %)
4 (8 %)
44 (45.4 %)
40 (41.2 %)
13 (13.4 %)
34 (55.8 %)
21 (34.4 %)
6 (9.8 %)
28 (54.9 %)
18 (35.3 %)
5 (9.8 %)
19 (45.2 %)
16 (38.1 %)
7 (16.7 %)
48 (51.1 %)
37 (39.3 %)
9 (9.6 %)
8 (50 %)
6 (37.5 %)
2 (12.5 %)
TCA + SIRS
2 (33.3 %)
4 (66.7 %)
10 (40 %)
11 (44 %)
4 (16 %)
11 (52.4 %)
7 (33.3 %)
3 (14.3 %)
1 (14.3 %)
4 (57.1 %)
2 (28.6 %)
38 (56.7 %)
23 (34.3 %)
6 (9 %)
9 (56.3 %)
6 (37.5 %)
1 (6.2 %)
2 (40 %)
3 (60 %)
For those who have suicide attempts history, 17.9 % of them have the TT genotype, and 50 % have CT genotype (p = 0.099) (Table 8). Moreover, we noticed that CC genotype is more frequent then CT and TT genotypes in patients who have atypical depression (55.6 %) with medium severity (71.4 %) which associated to anxiety (54.1 %) specially panic one (67.7 %). In addition, we found that CC genotype is also more frequent with patients who have depression Cluster C (Table 8). Depressive patients, who have CT genotype, are frequently treated by Mixed Antidepressant (selective inhibitors of serotonin reuptake, tricyclic antidepressant) and usually use sertraline (Table 8).
To our knowledge, no study was done in Tunisian depressed population related to the C677T polymorphism. A significant association was found between age and pathology, The patients have the highest mean age with 44.11 ± 13.52 years, and the pathology is associated with the oldest cohort of our population (>50 years) with p = 0.021. Elderly person have many difficulties with activities of daily living, and many studies demonstrated that this difficulties are associated with increase of depressive symptoms increased with age . Our result can be explained also by the higher levels of homocysteine usually in depressed subjects compared to controls. The plasma level of homocysteine is influenced by factors such as age, so it is possible that such effects contribute to the cascade of events leading to depression in later life .
We have not found any association between MTHFR polymorphism and unipolar depression, this result is similar to the findings of Kunugi et al.  and Henriquez-Hernandez et al. . In a cohort of 277 Slovak with 143 controls subjects and 134 depressed patients, Evinova et al.  did not find any significant association with this polymorphism and major depressive disorders. On the other hand, meta-analysis of 26 studies, conclude that the MTHFR C677T is associated with increased risk of depression . Reif et al. , have found a positive association between the same MTHFR polymorphism and Major depressive disorder.
In our study, CT genotype was more frequent and significantly in controls than depressives and after adjustment, this association remained significant. So CT genotype may be protecting from depression. This result is annoyed by the work of Shen et al. , who examined 368 patients and 219 controls, and he found a positive association between the CT genotype (p < 0.001) and depression.
Arinami et al.  have been the first ones who focused on this gene polymorphism, and found that TT genotype has a higher prevalence with depression with 2.8 as odd ratio. The same result was found in the meta-analysis of 17 articles by Peerbooms et al.  suggesting that TT genotype increase risk of receiving the diagnosis of major depressive disorders.
On the other hand, Bjelland et al. , report a positive association between TT genotype and higher level of homocysteine with depression without comorbid anxiety disorder. In Slovak population, TT genotype of C677T and AC genotype of A1298C of BDNF gene are considerably associated with the higher risk of major depression disorders .
In Poland population, Chojnicka et al. , have not found any association between the polymorphism and completed suicide, the same result is found in our study. A lake of association is supported by several studies [21, 23, 28–31]. The same contradictory results are shown in meta-analysis, Gilbody et al. , Lok et al. , López-León et al.  and Wu et al.  indicate that TT genotype increase the risk of depression disorders but Gaysina et al.  and Zintzaras , confirmed a lake of signification between the polymorphism and the pathology.
These controversial results may be due to the small sample sizes or to the influence of ethnic and demographic differences. Wu et al.  found that MTHFR C677T polymorphism is correlated to depression of Asian population in all genotype models, but only a marginal correlation was observed among white populations in recessive model. He showed that Asian population had a greater genetic risk to develop depression in comparison with white population. This also can be explained by the nature of food which is fortified with folate, so the TT effect cannot be observed .
According to gender, no association was found in men between depression and C677T, but in women, we found a positive association (χ 2 = 8.921, df = 2, p = 0.012) and that TT genotype increase the risk of developing depression by four times referring to CC genotype with (p = 0.053 and p* = 0.082 before and after adjustment). These results show a greater genetic risk in women to develop depression.
Słopien et al.  found a higher correlation with TT genotype and depression found in post menopausal women (OR = 3.478; 95 % CI = 1.377–8.783; p = 0.0096), and this genotype displayed about 4.8-fold increased risk of moderate and severe depression (CI 95 % = 1.975–11.820, p = 0.0008). This association is confirmed by the work of Lewis et al.  on British Women’s Heart and Health Study with 545 women (OR = 1.35, 95 % CI = 1.1–1.8). It’s not supported by Kempisty et al.  who found a higher percentage of T allele in men compared to women and suggest that the 667T allele might represent a minor liability in women or an increased survival advantage for men.
No association is found in the work of Gaysina et al.  between depressive women and C677T polymorphism with (χ 2 = 2 1.5; ddl = 2; p = 0.47) but Almeida et al.  did not find association in older women. Focusing on demographic characters, we find that CT genotype seems to be associated with addictive behavior in depressed people .
In our population, the major frequency of alcohol consumers, drugs abuse and smokers has a CT genotype who has been demonstrated previously as a protector from depression. We can explain this result by the neutralization of the protective effect of the CT genotype by the addictive behavior and the gene environment interaction. Patients need a good lifestyle to be protected, without addictive behavior that can change the gene effect.
Otherwise these associations can be explained by the relation between the levels of homocysteinemia and C677T genotype. Hultberg  demonstrated that chronic alcoholism was associated with hyperhomocysteinemia. On the other side Benyamina et al.  suggest that MTHFR 677TT genotype could play a protective role against alcohol dependence.
Lok  suggest that the interaction between MTHFR C677T and cannabis increased risk of recurrence in recurrent major depressive disorder patients over 5.5 years of follow-up and is associated with depressive symptoms in the general population. The study of Guillem et al.  confirms the high mood and anxiety disorders comorbidity among dependent users of cannabis. Also there are also studies that is showing low folate level due to cannabis abuse in pregnant women  and undergraduate students . Cannabis abuse is associated with higher Homocysteine, as well as lower HDL and vitamin B12 levels first-episode schizophrenia .
Smoking is also associated with depression, and smoking is known to be associated with higher homocysteine plasma levels . Moreover, Brown  confirms that the T allele and smoking interact in their association with homocysteine plasma levels. The T allele in smoking group had the highest level of homocysteine, in the opposite of C allele who had the lowest levels of homocysteine plasma.
Variant alleles (CT, TT) have been linked with increased serum homocysteine concentrations [47, 48], so this association can be explained by the gene environment influence on homocysteine level and cause depression, and we think that drugs, alcohol and smoking intake interfere with folate metabolism and affect the level of homocysteinemia.
No significant association was found between rs1801133 (C677T) polymorphism and suicide behavior (p = 0.682), suicide ideation (p = 0.603) and suicide attempts (p = 0.629) . In Polish Caucasians population, MTHFR C677T polymorphism is admitted like not a risk factor for completed suicide with TT .
No significant association was found between treatment and MTHFR C677T polymorphism, but CT genotype was more frequent in patient, who use of the mixed antidepressant. This choice by doctors can be explained by the responses of depressive patients to the treatment. In literature, Shen et al.  report in Chinese Han population that MTHFR C677T interact with COMT Val158Met, to increase Major depressive disorder but without influencing on treatment responses. Bousman et al.  show the absence of remission for patients who have CC genotype after treatment. This contradiction may be explained by the influence of environmental factors, genetic variant interaction and socio-demographical interaction.
This paper is the first study to prove that in Tunisian population of center region exist positive associations between depressive disorder and the C677T polymorphism and especially with CT and TT genotype. In our population, the more a person becomes aged, the more he is risked to have this pathology. In our case of study, we found that TT genotype is associated with depression and this association is more frequent in women, more than in men. In another hand, we considered that CT genotype is a protector from depression; however, major frequency of alcohol consumers, drugs abuse and smoking patients has a CT genotype, so it is no longer a protector because it seems that it is associated with addictive behavior in depressed people.
So this genotype may be used as a genetic marker to identify a patient with a higher risk of development of depressive disorder for better therapeutic management and prevent disease installation through treatment, psychological support and nutrition. But this study must be confirmed with other works with larger population.
More genetic and biochemical investigations are recommended to have a better comprehension for this disease. A detection particular with combination of polymorphism of different genes may confer a better exploration of earlier onset or presence of the different forms of pathology. Further studies of genetic polymorphism and a possible correlation with pathology, may lead to discover a novel marker to identify a patient with a higher risk of development of depressive disorder.
MAS conceived the study, gathered and managed the data, carried out the genetic study, performed the literature search and statistical analysis and wrote the paper. OA participated in the genetic study in lab, in the management of the data, statistical analysis and writing of the paper. AE, IH participated in the Literature search, the management of the data, statistical analysis and writing of the paper. AO, WD, MFN participated in designing the study, analysing the data, writing the paper and in correction of the final manuscript. LG contributed to the clinical and rating evaluations during the follow-up periods. All authors read and approved the final manuscript.
The authors thank the patients and control subjects for their assistance in this study.
The authors declare that they have no competing interests.
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- Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11–53.View ArticlePubMedGoogle Scholar
- Szabo ST, Nemeroff CB. Depression. In: Rosenberg RN, Pascual JM, editors. Rosenberg’s molecular and genetic basis of neurological and psychiatric disease. 2015. p. 1253–74.Google Scholar
- Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJL, Vos T, Whiteford HA. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:e1001547.View ArticlePubMedPubMed CentralGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- López-León S, Janssens ACJW, Ladd AGZ, Del-Favero J, Claes SJ, Oostra BA, van Duijn CM. Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry. 2008;13:772–85.View ArticlePubMedGoogle Scholar
- Bjelland I, Ueland PM, Vollset SE. Folate and depression. Psychother Psychosom. 2003;72:59–60.View ArticlePubMedGoogle Scholar
- Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a huge review. Am J Epidemiol. 2006;165:1–13.View ArticlePubMedGoogle Scholar
- Kim JM, Bae KY, Yoo JA, Shin IS, Kim SW, Yang SJ, Youn T, Chung KH, Yoon JS. P.2.a.024 alcohol use disorder and its associations with polymorphisms on ALDH2, BDNF, 5-HTTLPR and MTHFR in older Korean men. Eur Neuropsychopharmacol. 2009;19:374.View ArticleGoogle Scholar
- Kim J-M, Stewart R, Kim S-W, Yang S-J, Shin I-S, Yoon J-S. Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. Br J Psychiatry. 2008;192:268–74.View ArticlePubMedGoogle Scholar
- Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MWP, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69:228–32.View ArticlePubMedPubMed CentralGoogle Scholar
- Folstein M, Liu T, Peter I, Buel J, Arsenault L, Scott T, Qiu WW. The homocysteine hypothesis of depression. Am J Psychiatry. 2007;164:861–7.View ArticlePubMedGoogle Scholar
- Engbersen AM, Franken DG, Boers GH, Stevens EM, Trijbels FJ, Blom HJ. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet. 1995;56:142–50.PubMedPubMed CentralGoogle Scholar
- Wu Y-L, Ding X-X, Sun Y-H, Yang H-Y, Chen J, Zhao X, Jiang Y-H, Lv X-L, Wu Z-Q. Association between MTHFR C677T polymorphism and depression: an updated meta-analysis of 26 studies. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:78–85.View ArticlePubMedGoogle Scholar
- Zintzaras E. Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis. J Hum Genet. 2006;51:618–24.View ArticlePubMedGoogle Scholar
- Gaysina D, Cohen S, Craddock N, Farmer A, Hoda F, Korszun A, Owen MJ, Craig IW, McGuffin P. 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 Neuropsychiatr Genet. 2008;147B:699–706.View ArticleGoogle Scholar
- Gerard N, Berriche S, Aouizerate A, Dieterlen F, Lucotte G. North African Berber and Arab influences in the western Mediterranean revealed by Y-chromosome DNA haplotypes. Hum Biol. 2006;78:307–16.View ArticlePubMedGoogle Scholar
- Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.View ArticlePubMedPubMed CentralGoogle Scholar
- Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111–3.View ArticlePubMedGoogle Scholar
- Singh A, Misra N. Loneliness, depression and sociability in old age. Ind Psychiatry J. 2009;18:51–5.View ArticlePubMedPubMed CentralGoogle Scholar
- Almeida OP, Flicker L, Lautenschlager NT, Leedman P, Vasikaran S, van Bockxmeer FM. Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life. Neurobiol Aging. 2005;26:251–7.View ArticlePubMedGoogle Scholar
- Kunugi H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T, Hirose T, Nanko S. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry. 1998;3:435–7.View ArticlePubMedGoogle Scholar
- Henriquez-Hernandez LA, Murias-Rosales A, Hernandez Gonzalez A, Cabrera De Leon A, Diaz-Chico BN, Mori De Santiago M, Fernandez Perez L. Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: a case-control study. Oncol Rep. 2009;22:1425–33.View ArticlePubMedGoogle Scholar
- Reif A, Pfuhlmann B, Lesch K-P. Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1162–8.View ArticlePubMedGoogle Scholar
- Shen X, Wu Y, Guan T, Wang X, Qian M, Lin M, Shen Z, Sun J, Zhong H, Yang J, Li L, Yuan Y. Association analysis of COMT/MTHFR polymorphisms and major depressive disorder in Chinese Han population. J Affect Disord. 2014;161:73–8.View ArticlePubMedGoogle Scholar
- Arinami T, Yamada N, Yamakawa-kobayashi K, Hamaguchi H, Toru M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997;528:526–8.View ArticleGoogle Scholar
- Peerbooms OLJ, van Os J, Drukker M, Kenis G, Hoogveld L, de Hert M, Delespaul P, van Winkel R, Rutten BPF. 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.View ArticlePubMedGoogle Scholar
- Chojnicka I, Sobczyk-Kopcioł A, Fudalej M, Fudalej S, Wojnar M, Waśkiewicz A, Broda G, Strawa K, Pawlak A, Krajewski P, Płoski R. No association between MTHFR C677T polymorphism and completed suicide. Gene. 2012;511:118–21.View ArticlePubMedGoogle Scholar
- Lan W-H, Yang AC, Hwang J-P, Hong C-J, Liou Y-J, Yeh H-L, Liu M-E, Tsai S-J. Association of MTHFR C677T polymorphism with loneliness but not depression in cognitively normal elderly males. Neurosci Lett. 2012;521:88–91.View ArticlePubMedGoogle Scholar
- Lok A, Mocking RJT, Assies J, Koeter MW, Bockting CL, de Vries GJ, Visser I, Derks EM, Kayser M, Schene AH. The one-carbon-cycle and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state? J Affect Disord. 2014;166:115–23.View ArticlePubMedGoogle Scholar
- Lizer MH, Bogdan RL, Kidd RS. Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in depressed versus nondepressed patients. J Psychiatr Pract. 2011;17:404–9.View ArticlePubMedGoogle Scholar
- Hong ED, Taylor WD, McQuoid DR, Potter GG, Payne ME, Ashley-Koch A, Steffens DC. Influence of the MTHFR C677T polymorphism on magnetic resonance imaging hyperintensity volume and cognition in geriatric depression. Am J Geriatr Psychiatry. 2009;17:847–55.View ArticlePubMedPubMed CentralGoogle Scholar
- Lok A, Assies J, Koeter MW, Bockting CL, Visser I, Moeton M. Interaction of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and folic acid levels in recurrent depression. J Affect Disord. 2008;107:S75.View ArticleGoogle Scholar
- Beardslee WR, Gladstone TRG, O’Connor EE. Developmental risk of depression: experience matters. Child Adolesc Psychiatr Clin N Am. 2012;21:261–78.View ArticlePubMedGoogle Scholar
- Słopien R, Jasniewicz K, Meczekalski B, Warenik-Szymankiewicz A, Lianeri M, Jagodziński 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.View ArticlePubMedGoogle Scholar
- Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day INM, Ebrahim S. 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.View ArticlePubMedGoogle Scholar
- Kempisty B, Mostowska A, Górska I, Łuczak M, Czerski P, Szczepankiewicz A, Hauser J, Jagodziński PP. Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Neurosci Lett. 2006;400:267–71.View ArticlePubMedGoogle Scholar
- De Almeida-paula LD, Costa-lotufo LV, Silva Z, Elisa A, Monteiro G, Cesar M, Godinho RO, Markus RP. Melatonin modulates rat myotube-acetylcholine receptors by inhibiting calmodulin. Eur J Pharmacol. 2005;525:24–31.View ArticleGoogle Scholar
- Hultberg B, Berglund M, Andersson A, Frank A. Elevated plasma homocysteine in alcoholics. Alcohol Clin Exp Res. 1993;17:687–9.View ArticlePubMedGoogle Scholar
- Benyamina A, Saffroy R, Blecha L, Pham P, Karila L, Debuire B, Lemoine A, Reynaud M. Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typology. Addict Biol. 2009;14:503–5.View ArticlePubMedGoogle Scholar
- Lok A, Bockting CLH, Koeter MWJ, Snieder H, Assies J, Mocking RJT, Vinkers CH, Kahn RS, Boks MP, Schene AH. Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression. Transl Psychiatry. 2013;3:e288.View ArticlePubMedPubMed CentralGoogle Scholar
- Guillem E, Arbabzadeh-Bouchez S, Vorspan F, Bellivier F. Comorbidités chez 207 usagers de cannabis en consultation jeunes consommateurs. Encephale. 2015;41(Suppl 1):S7–12.View ArticlePubMedGoogle Scholar
- Knight EM, James H, Edwards CH, Spurlock BG, Oyemade UJ, Johnson AA, West WL, Cole OJ, Westney LS, Westney OE. Relationships of serum illicit drug concentrations during pregnancy to maternal nutritional status. J Nutr. 1994;124(6 Suppl):973S–80S.PubMedGoogle Scholar
- Davis RE, Midalia ND, Curnow DH. Illegal drugs and nutrition in undergraduate students. Med J Aust. 1978;1:617–20.PubMedGoogle Scholar
- Misiak B, Frydecka D, Slezak R. Elevated homocysteine level in first-episode schizophrenia patients—the relevance of family history of schizophrenia and lifetime diagnosis of cannabis abuse. Metab Brain Dis. 2014;29:661–70.View ArticlePubMedPubMed CentralGoogle Scholar
- Cassidy K, Kotynia-English R, Acres J, Flicker L, Lautenschlager NT, Almeida OP, Cassidy K, Kotynia-English R, Acres J, Flicker L, Lautenschlager NT, Almeida OP. Association between lifestyle factors and mental health measures among community-dwelling older women. Aust New Z J Psychiatry. 2004;38(11–12):940–7.View ArticleGoogle Scholar
- Brown KS, Kluijtmans LAJ, Young IS, Murray L, McMaster D, Woodside JV, Yarnell JWG, Boreham CA, McNulty H, Strain JJ, McPartlin J, Scott JM, Mitchell LE, Whitehead AS. The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine. Atherosclerosis. 2004;174:315–22.View ArticlePubMedGoogle Scholar
- Tokgözoğlu SL, Alikaşifoğlu M, Unsal, Atalar E, Aytemir K, Ozer N, Ovünç K, Usal O, Kes S, Tunçbilek E. Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate. Heart. 1999;81:518–22.View ArticlePubMedPubMed CentralGoogle Scholar
- Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93(1):7–9.View ArticlePubMedGoogle Scholar
- Bousman CA, Potiriadis M, Everall IP, Gunn JM. Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: a five-year prospective cohort study of primary care attendees. Am J Med Genet Part B Neuropsychiatr Genet. 2014;165:68–76.View ArticleGoogle Scholar