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 B Neuropsychiatr Genet 147B:699-706

MRC SGDP Centre, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 09/2008; 147B(6):699-706. DOI: 10.1002/ajmg.b.30665
Source: PubMed


Unipolar major depressive disorder (MDD) is a complex disorder thought to result from multiple genes in combination with environmental and developmental components. The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been implicated in MDD in a meta-analysis of association studies and is within a linkage region suggested by a recent study of affected sib pairs. A single base mutation in the MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme. The MTHFR 677TT genotype, and to a lesser extent the 677CT genotype, is associated with a significant elevation in the circulating concentrations of homocysteine and a decrease in serum folate concentrations. This may parallel a similar reduction in 5-methyltetrahydrofolate in the CNS, leading to a potential reduction in monoamine neurotransmitter function and an elevated risk of depressive disorder. To test the hypothesis that the MTHFR C677T polymorphism is involved in the predisposition to MDD, we conducted an association study of 1,222 patients with recurrent MDD and 835 control subjects. This allows 99% power to detect an effect of the size reported in the study of Bjelland et al. 2003, however no significant differences in genotype or allele frequencies between depressive patients and controls were observed. This was the case in the sample as a whole, and when females and males were considered separately. Our findings suggest that the MTHFR C677T polymorphism is not involved in the etiology of clinically significant recurrent MDD.

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    • "Even metaanalyses on this topic have produced conflicting results. Despite some meta-analyses supporting the hypothesis of a higher risk of the MTHFR 677TT genotype in developing MDD (Gilbody et al., 2007; Peerbooms et al., 2011; Wu et al., 2013), others have not confirmed this association (Zintzaras, 2006; Gaysina et al., 2008). "
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    ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) genetic variations have been widely studied in major depressive disorder (MDD) and antidepressants outcome. An interaction with catechol-O-methyltransferase (COMT) has also been proved affecting depression. The aim of this study was to clarify the role of the most commonly studied single nucleotide polymorphisms (SNPs) of MTHFR gene in MDD and in treatment response mechanisms, along with the impact of the interaction with COMT. A total of 613 MDD patients, of whom 389 were classified as having treatment resistant depression (TRD), and 463 controls were enrolled. The A1298C, C677T and COMT Val158Met were genotyped. Genetic data were integrated with a transcriptional level analysis in peripheral blood cells (PBCs) and fibroblasts. The A1298C CC homozygotes were more frequent in MDD patients compared to controls in women, increasing twice the genetic risk to develop depression. Moreover this genotype resulted in epistasis with COMT Met carriers in association with MDD. No significant effects were obtained concerning response to treatment. Transcriptional analyses highlighted a strong correlation between the mRNA levels of MTHFR in fibroblasts and COMT genotypes whereas no significant association with MDD was found. PBCs results revealed relevant influences of environmental factors. We did not measure folate and homocisteine levels. This study showed the involvement of A1298C, Val158Met and their interaction in MDD. The transcriptional analyses supported the participation of COMT in the folate pathway, which partakes in the complex network of gene×gene and gene×environment interactions of MDD etiopathogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 05/2015; 183. DOI:10.1016/j.jad.2015.05.003 · 3.38 Impact Factor
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    • "For MTHFR C677T, three studies confirmed the T allele or CT/TT genotypes in MDD in mixed ethnic cohorts (Gilbody et al., 2006; Lewis et al., 2006; Lopez-Leon et al., 2008) (Supplementary Table 1), but one study reported conflicting null effects in mixed ethnic samples for the T allele and TT genotype (Zintzaras, 2006), albeit in much smaller cohorts relative to the significant studies suggesting that the conflicting results may be due to reduced power in the null studies (Supplementary Table 3). Two studies also reported null effects for these same alleles and genotypes but in Asian and Caucasian samples (Gaysina et al., 2008; Zintzaras, 2006) (Supplementary Table 2), suggesting the effect is only apparent in mixed ethnic groups. For 5-HTTLPR, three studies confirmed the S allele or SS genotype in MDD in mixed (Lopez-Leon et al., 2008) and Caucasian samples (Furlong et al., 1998; Kiyohara and Yoshimasu, 2010). "
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    ABSTRACT: Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
    Journal of Psychiatric Research 09/2014; 60. DOI:10.1016/j.jpsychires.2014.09.014 · 3.96 Impact Factor
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    • "Two meta-analyses indicated that the MTHFR TT-homozygous genotype increases MDD-risk (Gilbody et al., 2007; López-León et al., 2007). However, two other meta-analyses found no association between MTHFR-gene variants and MDD (Gaysina et al., 2008; Zintzaras, 2006). A recent meta-analysis of all published case-control studies investigating MTHFR C677T in 9648 patient and 19,854 control subject showed that T-allele carriers and TT-genotype are at a small (odds ratio ¼ 1.26) but significant increased risk of major psychiatric disorders like schizophrenia, bipolar disorder and unipolar MDD (Peerbooms et al., 2011). "
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    ABSTRACT: Background An important biological factor suggested in the pathophysiology of (recurrent) Major Depressive Disorder (MDD) concerns a polymorphism in a gene encoding for the MTHFR-enzyme of the one-carbon (1-C)-metabolism. Integratively investigating key 1-C-components (folate, homocysteine, vitamin B6 and B12), including the possible effects of antidepressant medication and depressive state, could provide more insight in the possible association between the MTHFR-polymorphism and recurrent MDD. Methods We compared the MTHFR C677T-polymorphism together with the key 1-C-components in clinically ascertained patients with recurrent MDD (n=137) to age- and gender-matched healthy controls (n=73). Results First, patients had lower folate (t=2.25; p=.025) as compared to controls; a difference that resolved after correction for demographics (t=1.22; p=.223). Second, patients that were depressed during sampling had lower vitamin B6 (t=−2.070; p=.038) and higher homocysteine (t=2.404; p=.016) compared to those in remission. Finally, current use of antidepressants had no influence on the 1-C-components. Conclusions Despite investigation of a specific recurrently depressed patient population, we found no clear associations with the 1-C-cycle, except for higher homocysteine and lower vitamin B6 during the depressed state. This suggests that 1-C-cycle alterations in MDD are state-associated, possibly resulting from high levels of acute (psychological) stress, and may provide a treatment target to reduce cardiovascular risk in this population.
    Journal of Affective Disorders 09/2014; 166:115–123. DOI:10.1016/j.jad.2014.04.048 · 3.38 Impact Factor
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