Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis
© Samaan et al; licensee BioMed Central Ltd. 2011
Received: 16 December 2010
Accepted: 2 June 2011
Published: 2 June 2011
Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date.
Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine.
MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63).
MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.
Migraine is a common primary headache disorder characterised by recurrent headaches associated with gastrointestinal, neurological and autonomic symptoms . Migraine is sub classified further into several types, the most commonly noted are migraine with aura (MA) where aura symptoms, usually visual, precede the headache, and migraine without aura (MO). These common types of migraine are often reported to co occur with depression [2–5] making the screening for migraine in individuals with depression and vice versa an important clinical assessment with impact on diagnosis, treatment and prognosis. The screening for migraine in depression also has a significant impact for research where the findings may be confounded by the presence of another disorder. It is known that both conditions have a genetic background [6–8]. A common polymorphism from the MTHFR gene, the C677T, has been reported to be associated with both migraine and depression independently. The MTHFR gene is located on chromosome 1p36.3 and encodes for a key enzyme for the metabolism of folate and homocysteine . The MTHFR 677C to T transmission is characterized by a point mutation resulting in a valine substitution for an alanine in this enzyme. Individuals with the homozygous (TT) state for this mutation showed higher levels of plasma homocysteine . Homocysteine acts as an excitatory amino acid and may influence the threshold for migraine headache. High homocysteine levels are seen in individuals with migraine with aura .
To our knowledge previous studies have investigated this gene variant in either cases of depression alone, or migraine alone without controlling for the presence of the other condition. We hypothesize that the MTHFR C677T polymorphism is a migraine gene and the association with depression is due to the presence of migraine in the individuals studied. In this study, we investigate the association between MTHFR C677T polymorphism and migraine in a sample of cases of depression and healthy controls. A meta-analysis of studies of this variant and migraine is also reported.
1. Case Control Study
The study subjects were recruited for a genetic case-control association study of recurrent major depression, the Depression Case Control study (DeCC). The sample selection and recruitment have been described in detail . Briefly, depression cases (18 years or older) of Caucasian origin with a recurrent depressive disorder were recruited from 3 sites in the UK (London, Cardiff and Birmingham). Control subjects were selected from the UK general practice based GENESiS study  and were included in the study if they were of Caucasian origin with no past or current psychiatric disorder. All subjects gave written informed consent. Local ethics committees of the study centres approved the study.
All depression cases were given a face to face diagnostic interview, the Schedule for Clinical Assessment in Neuropsychiatry (SCAN) , administered by trained interviewers to establish the diagnosis of recurrent depression. Control subjects were interviewed by telephone using the Past History Schedule  and were included if there was no evidence of past or present psychiatric disorder.
For the lifetime diagnosis of migraine the structured migraine interview (SMI)  based on the ICHD  was used. Detailed questions about the presence of headache, severity, frequency, duration, site, type, aura symptoms and associated symptoms (nausea, vomiting, sensitivity to light and sound) were obtained. Depression cases were interviewed face to face and the control subjects were interviewed by telephone. Subjects were assigned a diagnosis of MA, MO, probable migraine (PM), no recurrent headaches and non-migraine headaches.
DNA samples were obtained from whole blood or buccal epithelial cells for molecular genetic analysis. Whole blood samples were collected at the time of the interview for all cases with depression that consented for the genetic portion of the study. Interviewers collected 25 ml of blood from peripheral veins in the anticubital fossa. Blood samples were collected in Monovettes tubes containing EDTA. Each tube was rolled gently after blood collection was completed and stored at room temperature until the end of the interview where it was then transferred to the local lab for storage at -20°C freezer in upright position. In addition, blood drops from Monovettes tubes were placed on Buffy Coat. All samples (tubes and Buffy Coat) were labelled with a unique ID number and bar codes were placed on the tubes and Buffy Coat. Control subjects were sent cheek swabs (labelled with unique barcode ID) and instructions on how to obtain buccal swab samples and were supplied with return addressed envelopes. DNA was extracted in house from both whole blood and buccal mucosa samples following validated procedures as described earlier . Genotyping of the MTHFR C677T SNP rs1801133 was performed by KBioscience (Hoddesdon, Hertz, UK, http://www.kbioscience.co.uk), blinded to the phenotype status. Full details of the genotyping methods and primers design were previously described .
Data were entered into SPSS version 14 for Windows and statistical analyses were performed using chi square statistic and logistic regression analysis. Genotype and allele frequencies were investigated for association with migraine using contingency tables and chi square statistic. To test for specific association between MA and MTHFR C677T, logistic regression was used with MA as dependent variable and age, sex and depression were entered as co variables.
Migraine and MTHFR case control studies
105 (90 MO and 15 MA)
MA: 2.16 (0.64-7.41) MO: 2.04 (0.98-4.22)
33 (5-17 yr old)
2.18 (0.68, 7)
USA Caucasian female only
93(23 MA; 70 MO)
MA: 3.05 (0.39-24.51) MO: 7.44 (1.70-32.34)
230 (78 MA and 152 MO)
MA: 1.37 (0.63-2.94) MO: 0.59 (0.27-1.24)
329 (138 MA and 191 MO)
MA: 2.4 (0.8-7.2) MO: 0.28 (0.1-0.8)
0.98 (0.84-1.15) "c"
Statistical heterogeneity across studies was assessed using the Q statistic, with significant heterogeneity for all of the migraine outcomes. Summary estimates were calculated using a general variance-based method (random-effects model) with 95% CI . Stratified analyses were also conducted by ethnic ancestry (European or non-European). Since one study included women participants only, a sensitivity analysis was conducted whereby this one study was excluded from the analysis to determine whether the parameter estimates are altered.
No Migraine N = 1402
Any Migraine N = 447
Female N [%]
Depression N [%]
Married/cohabiting N [%]
≥ 1 Child N [%]
Currently employed N [%]
≥ 12 years education N [%]
Age in year [SD]
47.7 [± 11.14]
46.9 [± 11.7]
Genotype and allele frequencies for the MTHFR gene C677T SNP were analysed for 810 (95% genotyping reaction success) psychiatrically healthy controls and 1039 (83% genotyping success rate) depression cases. The controls' genotype frequencies were in Hardy-Weinberg Equilibrium (HWE) (χ2 = 0.01, df = 1, p = 0.92).
MTHFR C677T polymorphism and migraine
Allele and genotype frequencies for the MTHFR C677T variant were investigated in migraine. Migraine categories were assigned as follows:
No migraine headache including no recurrent headache and non-migraine headaches.
Migraine including MA, MO and PM.
rs1801133 genotype and allele frequency
No Migraine N [%]
Any Migraine N [%]
Migraine with Aura N [%]
The effect of sex was explored in the analysis and showed excess T allele frequency in women with MA (χ2 = 8.22, df = 1, p = 0.004, OR = 1.53, 95% CI 1.13 - 2.07) and TT genotype (χ2 = 7.47, df = 1, p = 0.006, OR = 2.20, 95% CI 1.19 - 4.07).
Summary results of logistic regression analysis.
All studies (15 [100%]) (Table 1) assessed MA, while some (4 [26.7%]) also evaluated MO, and 1 (6.7%) examined tension headache. In total, the 15 studies included N = 4,374 migraine cases and N = 30,110 controls. Table 1 summarizes the characteristics and results of the included case-control studies by migraine type. Among the 15 studies included in the meta-analysis, 12 studies enrolled participants of European ancestry, while 3 studies recruited participants of non-European ancestry. Almost all of the studies (14 [93.3%]) included both men and women.
Meta-analysis summary odds ratios (95% CI) for the association of the T allele homozygosity with migraine
N = 4,365 cases
N = 3,862 cases
N = 503 cases
N = 30,110 controls
N = 30,110 controls
N = 674 controls
1.37 (1.07-1.76) "a"
1.42 (1.10-1.82) "a"
Excluding 1 study of women only "b"
1.46 (1.11-1.92) "a"
1.54 (1.17-2.02) "a"
1.28 (1.002-1.63) "a"
3.46 (1.22-9.82) "a"
Table 5 shows the summary estimates for each migraine type by ethnic origin. In studies of European ancestry, there was a significant association between TT genotype and MA (OR = 1.28; 95% CI, 1.002-1.63), but not with MO (OR = 0.73; 95% CI, 0.24-2.24) or total migraine (OR= 1.20; 95% CI, 0.95-1.53). Conversely, in studies of non-European origin, the TT genotype was not significantly associated with MA (OR = 2.81; 95% CI, 0.84-9.44) but was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), and there was only 1 study that evaluated MO.
We report a significant association between a common SNP (rs1801133) in the MTHFR gene and MA in a well-characterized sample of depressed cases compared to psychiatrically healthy controls. Previous reports have shown an association between this SNP and depression. In fact, the association between MTHFR polymorphism and MA remained significant after adjusting for depression suggesting that this association is unique to MA. No statistically significant association was seen between this SNP and depression or MO in this study. The association between MTHFR C677T polymorphism and MA was stronger in women, however remained significantly associated with MA after controlling for sex, age and depression. Several studies suggested an association between MTHFR C677T polymorphism and migraine as described earlier. Similarly, our meta-analysis of 15 case-control studies showed that the T allele is significantly associated with MA and total migraine, the association with total migraine is most likely accounted for by the presence of migraine with aura. Conversely other studies found the TT genotype protective for MA [26–29]. A meta analysis  pooled data from 2961 cases of migraine reported a significant association between TT genotype and MA only (OR 1.30, 95% CI 1.06-1.58). More recently, a meta-analysis of studies published up to March 2009, reported a significant association between migraine with aura and MTHFR C677T polymorphism (OR 1.48, 95% CI 1.02-2.13) that was mainly driven by non-Caucasian populations . Our meta-analysis included 2 additional studies and found that this genetic variant is associated with total migraine in non-Caucasian populations and with migraine with aura in Caucasians. Furthermore, it has been suggested that this polymorphism was also associated with depression [18, 32–35], we have reported previously that there was no significant association between depression and this SNP  and we argue that the previous reports of MTHFR C677T association with depression can be explained by the high prevalence of migraine in depressed subjects included in these studies. None of the studies reported have screened subjects for migraine. Since migraine can be present in almost a third of participants , it is likely that the association between MTHFR C677T and depression is actually an association with migraine.
In this depression case control study, we found migraine to be significantly associated with excess T allele and TT genotype of the MTHFR C677T polymorphism. This association was specific only to MA. Broad migraine (including MA, MO and PM) was not significantly different than non-migraine headaches in their T allele and TT genotype distribution. This trend was also shown in previous studies in different populations as described earlier. The results were not always consistent however and other studies reported negative findings. A relatively large study failed to show an association between migraine and MTHFR C677T polymorphism . Such contradictions can be explained in part by methods of identification of migraine, the different populations (clinical, epidemiological samples), age and sex of the study participants, ethnic variations and geographic sites included in these studies. Studies have shown that there are genetic variations across different populations and geographic locations; these variations may have a significant role in genetic studies findings when different populations were included. A small Japanese study (n = 22) was the first to report a significant association between MTHFR C677T and MA  replicated by several other small studies (Korean n = 34 , Spanish n = 60  and Italian n = 33 ) while large German (n = 656) and Finish (n = 898) studies failed to show significant association between MA and this polymorphism [16, 17]. These observations were in parallel with our meta-analysis by subgroups, which showed a strong and significant association between TT genotype and migraine in non-Europeans, although we also observed a modest but significant association with MA among Caucasians. This ethnic specific association between a genetic variant and phenotype highlights the importance of ethnic variations in genetic studies and the need to expand studies beyond one ethnic group. In addition, ethnic variation may be a reflection of health behaviour and life style factors such as dietary habits and policies on folic acid fortification of diet and supplements. In addition to the different population studied, there is also a significant variation in migraine case identification that added further heterogeneity to the reported studies. The diagnosis of migraine, like depression, is mainly based on careful history taking of specific symptoms that show repeated patterns over time and lack of significant findings in physical examination. Objective measures to confirm or deny the diagnosis of migraine are not yet available and therefore the methods of identification of migraine cases are important sources of heterogeneity and conflicting results in the literature of migraine genetics. Our findings of significant association between MA and MTHFR C677T in a well characterised study of 1849 subjects (migraine cases = 447) replicates earlier studies of moderate size [13, 14, 39] suggesting a role for the MTHFR gene in migraine especially MA. Further meta analysis of 13 studies reported a pooled OR = 1.48, 95% CI 1.02-2.13, for MA only . This may also indicate that the MTHFR gene effect is associated with aura symptoms specifically rather than migraine in general. It will be interesting to investigate homocysteine (a risk factor for stroke ) and folate levels, low folate levels have been reported in depression , in subjects with migraine with aura to confirm the association between MTHFR mutation and its function by measuring the end products of the enzyme. A small open label trial of folic acid administration in children with migraine, hyperhomocysteinaemia and MTHFR C677T polymorphism (TT genotype) reported a reduction in migraine symptoms in this population . In a study of 136 individuals with migraine with aura compared to controls, homocysteine level was higher in the migraine group . The homocysteine level was also higher in MA compared to MO . Randomized controlled trials are needed to confirm such findings, the results of which will be valuable for clinical practice in the management of migraine and depression.
Our results showed that excess T allele and homozygous TT genotype of the MTHFR gene C677T polymorphism is associated with increased risk for MA regardless of depression status. Our case control study showed that individuals carrying this genetic variant are 30% more likely to have migraine with aura and meta-analysis strengthened this observation and reported 42% increase in risk for such individuals, however it is important to keep in context that this 42% risk increase for MA is only in individuals carrying this genetic variant, the number of which is relatively small compared to the general population. The importance of our findings can be focused into 2 main areas:
1st studies of the MTHFR C677T variant are common especially in psychiatric and cardiovascular fields. These studies, we encourage, must take into consideration the common co occurrence of migraine in these disorders and the strong and reproducible association between this variant and migraine with aura. It is advisable therefore to screen and adjust for migraine in these studies to avoid spurious associations.
2nd individuals carrying this variant (although a small number of individuals are carrying the TT genotype variant) are at 42% increased risk for migraine with aura. In the light of increasing interests in personalised medicine, adding folate supplements to individuals at risk (a specifically targeted intervention for population at risk) may mitigate future development of migraine with aura.
The main strengths of our study are the use of validated diagnostic tool to identify migraine and the use of direct interviewing of all participants. Our study participants are also relatively homogenous (of Caucasian ethnicity, residing in the UK) thus reducing population stratification that can have a confounding effect. There are however certain weaknesses to our study. The study recruitment was designed to select depressed cases, which may have led to ascertainment bias. However migraine was systematically screened for in all participants and we have adjusted for depression status in our analysis. In addition our sample size did not allow for subgroup analysis of each headache type and therefore we are not able to report whether there is any association between this SNP and other types of primary headache disorders in addition to MA such as tension type headache.
The current study adds to the growing evidence for the role MTHFR C677T gene variant in migraine with aura. Our meta-analysis showed a significant association between this genetic variant and MA in Caucasian population and overall migraine in non-Caucasian population, although the effect in this case is very likely to be due to MA than migraine in general. Heterogeneity of studies remains a significant cause of conflicting results and ethnic variations in genotype-phenotype association must be examined closely.
migraine with aura
migraine without aura
methylene tetrahydrofolate reductase
single nucleotide polymorphism
Study Funding: Medical Research Council (MRC)
- ICHD-II: The International Classification of Headache Disorders. 2nd Edition. Cephalalgia. 2004, 24 (s1): 8-160.Google Scholar
- Samaan Z, Farmer A, Craddock N, Jones L, Korszun A, Owen M, Williamson R, McGuffin P: A Case- Control Study of Migraine in Recurrent Depression. British Journal of Psychiatry. 2009, 194: 350-354. 10.1192/bjp.bp.108.054049.View ArticlePubMedGoogle Scholar
- Merikangas KR: Psychopathology and headache syndromes in the community. Headache. 1994, 34 (8): S17-S22. 10.1111/j.1526-4610.1994.hed3408s17.x.View ArticlePubMedGoogle Scholar
- Breslau N, Lipton R, Stewart W, Schultz L, Welch K: Comorbidity of migraine and depression. Investigating potential etiology and prognosis. Neurology. 2003, 60: 1308-1312.View ArticlePubMedGoogle Scholar
- Lipton R, Hamelsky S, Kolodner K, Steiner TJ, Stewart W: Migraine, quality of life, and depression. Neurology. 2000, 55: 629-635.View ArticlePubMedGoogle Scholar
- Ball HA, Samaan Z, Brewster S, Craddock N, Gill M, Korszun A, Maier W, Middleton L, Mors O, Owen MJ, Perry J, Preisig M, Rice J, Rietschel M, Jones L, Jones I, Farmer AE, McGuffin P: Depression, migraine with aura and migraine without aura: their familiality and interrelatedness. Cephalalgia. 2009, 29 (8): 848-854. 10.1111/j.1468-2982.2008.01808.x.View ArticlePubMedGoogle Scholar
- Kendler KS, Prescott CA: A Population-Based Twin Study of Lifetime Major Depression in Men and Women. Arch Gen Psychiatry. 1999, 56 (1): 39-44. 10.1001/archpsyc.56.1.39.View ArticlePubMedGoogle Scholar
- Cologno D, De Pascale A, Manzoni GC: Familial Occurrence of Migraine With Aura in a Population-Based Study. Headache. 2003, 43 (3): 231-234. 10.1046/j.1526-4610.2003.03046.x.View ArticlePubMedGoogle Scholar
- Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuve LP, Rozen R: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet. 1995, 10 (1): 111-113. 10.1038/ng0595-111.View ArticlePubMedGoogle Scholar
- Moschiano F, D'Amico D, Usai S, Grazzi L, Di Stefano M, Ciusani E, Erba N, Bussone G: Homocysteine plasma levels in patients with migraine with aura. Neurological Sciences. 2008, 29 (0): 173-175.View ArticleGoogle Scholar
- Kara I, Sazci A, Ergul E, Kaya G, Kilic G: Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk. Brain Research Molecular Brain Research. 2003, 111 (1-2): 84-90.View ArticlePubMedGoogle Scholar
- Kowa H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K: The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. American Journal of Medical Genetics. 2000, 96 (6): 762-764. 10.1002/1096-8628(20001204)96:6<762::AID-AJMG12>3.0.CO;2-X.View ArticlePubMedGoogle Scholar
- Lea R, Ovcaric M, Sundholm J, MacMillan J, Griffiths L: The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. BMC Medicine. 2004, 2 (1): 3-10.1186/1741-7015-2-3.View ArticlePubMedPubMed CentralGoogle Scholar
- Scher AI, Terwindt GM, Verschuren WMM, Kruit MC, Blom HJ, Kowa H, Frants RR, van den Maagdenberg AMJM, van Buchem M, Ferrari MD, Launer LJ: Migraine and MTHFR C677T genotype in a population-based sample. Annals of Neurology. 2006, 59 (2): 372-375. 10.1002/ana.20755.View ArticlePubMedGoogle Scholar
- Oterino A, Valle N, Bravo Y, Munoz P, Sanchez-Velasco P, Ruiz-Alegria C, Castillo J, Leyva-Cobian F, Vadillo A, Pascual J: MTHFR T677 homozygosis influences the presence of aura in migraineurs. Cephalalgia. 2004, 24 (6): 491-494. 10.1111/j.1468-2982.2004.00692.x.View ArticlePubMedGoogle Scholar
- Todt U, Freudenberg J, Goebel I, Netzer C, Heinze A, Heinze-Kuhn K, Göbel H, Kubisch C: MTHFR C677T polymorphism and migraine with aura. Annals of Neurology. 2006, 60 (5): 621-622.View ArticlePubMedGoogle Scholar
- Kaunisto M, Kallela M, Hamalainen E, Kilpikari R, Havanka H, Harno H, Nissila M, Sako E, Ilmavirta M, Liukkonen J, Teirmaa H, Tornwall O, Jussila M, Terwilliger J, Farkkila M, Kaprio J, Palotie A, Wessman M: Testing of variants of the MTHFR and ESR1 genes in 1798 Finnish individuals fails to confirm the association with migraine with aura. Cephalalgia. 2006, 26 (12): 1462-1472. 10.1111/j.1468-2982.2006.01228.x.View ArticlePubMedGoogle Scholar
- Gilbody S, Lewis S, Lightfoot T: Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review. Am J Epidemiol. 2007, 165 (1): 1-13.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. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2008, 147B (6): 699-706. 10.1002/ajmg.b.30665.View ArticleGoogle Scholar
- Farmer A, Korszun A, Owen MJ, Craddock N, Jones L, Jones I, Gray J, Williamson RJ, McGuffin P: Medical disorders in people with recurrent depression. The British Journal of Psychiatry. 2008, 192 (5): 351-355. 10.1192/bjp.bp.107.038380.View ArticlePubMedGoogle Scholar
- Nash MW, Huezo-Diaz P, Williamson RJ, Sterne A, Purcell S, Hoda F, Cherny SS, Abecasis GR, Prince M, Gray JA, Ball D, Asherson P, Mann A, Goldberg D, McGuffin P, Farmer A, Plomin R, Craig IW, Sham PC: Genome-wide linkage analysis of a composite index of neuroticism and mood-related scales in extreme selected sibships. Hum Mol Genet. 2004, 13 (19): 2173-2182. 10.1093/hmg/ddh239.View ArticlePubMedGoogle Scholar
- Wing JK, Babor T, Burgha T: SCAN. Schedule for the Clinical Assessment of Neuropsychiatry. Archives of General Psychiatry. 1990, 47: 589-593.View ArticlePubMedGoogle Scholar
- McGuffin P, Katz R, Aldrich J: Past and present state examination: the assessment of 'lifetime ever' psychopathology. Psychological Medicine. 1986, 16 (2): 461-465. 10.1017/S0033291700009302.View ArticlePubMedGoogle Scholar
- Samaan Z, MacGregor EA, Dowson A, McGuffin P, Farmer A: Diagnosing migraine in research and clinical settings: development and validation of the Structured Migraine Interview (SMI). BMC Neurology. 2010, 10: 10-17. 10.1186/1471-2377-10-10.View ArticleGoogle Scholar
- DerSimonian R, Laird N: Meta-analysis in clinical trials. Controlled Clin Trials. 1986, 7: 177-188. 10.1016/0197-2456(86)90046-2.View ArticlePubMedGoogle Scholar
- Schurks M, Zee RYL, Buring JE, Kurth T: Interrelationships among the MTHFR 677C > T polymorphism, migraine, and cardiovascular disease. Neurology. 2008, 71 (7): 505-513. 10.1212/01.wnl.0000316198.34558.e5.View ArticlePubMedPubMed CentralGoogle Scholar
- Schürks M, Zee RYL, Buring JE, Kurth T: MTHFR 677CT & 2192;T and ACE D/I polymorphisms and migraine attack frequency in women. Cephalalgia. 2009Google Scholar
- Joshi G, Pradhan S, Mittal B: Role of the ACE ID and MTHFR C677T polymorphisms in genetic susceptibility of migraine in a north Indian population. Journal of the Neurological Sciences. 2009, 277 (1-2): 133-137. 10.1016/j.jns.2008.11.002.View ArticlePubMedGoogle Scholar
- Ferro A, Castro MJ, Lemos C, Santos M, Sousa A, Pereira-Monteiro J, Sequeiros J, Maciel P: The C677T polymorphism in MTHFR is not associated with migraine in Portugal. Disease Markers. 2008, 25 (2): 107-113.View ArticlePubMedPubMed CentralGoogle Scholar
- Rubino E, Ferrero M, Rainero I, Binello E, Vaula G, Pinessi L: Association of the C677T Polymorphism in the MTHFR Gene with Migraine: A Meta-Analysis. Cephalalgia. 2009, 29 (8): 818-825. 10.1111/j.1468-2982.2007.01400.x.View ArticlePubMedGoogle Scholar
- Schürks M, Rist PM, Kurth T: MTHFR 677C > T and ACE D/I Polymorphisms in Migraine: A Systematic Review and Meta-Analysis. Headache: The Journal of Head and Face Pain. 2010, 50 (4): 588-599. 10.1111/j.1526-4610.2009.01570.x.View ArticleGoogle 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. Molecular Psychiatry. 2006, 11 (4): 352-360. 10.1038/sj.mp.4001790.View ArticlePubMedGoogle Scholar
- Kelly CB, McDonnell AP, Johnston TG, Mulholland C, Cooper SJ, McMaster D, Evans A, Whitehead AS: The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004, 18 (4): 567-571. 10.1177/0269881104047285.View ArticlePubMedGoogle Scholar
- Arinami T, Yamada N, Yamakawa-Kobayashi K, Hamaguchi H, Toru M: Methylenetetrahydrofolate reductase variant and schizophrenia/depression. American Journal of Medical Genetics. 1997, 74 (5): 526-528. 10.1002/(SICI)1096-8628(19970919)74:5<526::AID-AJMG14>3.0.CO;2-E.View ArticlePubMedGoogle Scholar
- Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM: Folate, vitamin B12, homocysteine, and the MTHFR 677C- > T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Archives of General Psychiatry. 2003, 60 (6): 618-626. 10.1001/archpsyc.60.6.618.View ArticlePubMedGoogle Scholar
- Seo JH, Kim HJ, Lee IH, Kim OJ, Choi BO: Association between Migraine with Aura and both Homocysteine and MTHFR C677T Polymorphism. J Korean Neurol Assoc. 2004, 22 (3): 200-205.Google Scholar
- Oterino A, Valle N, Pascual J, Bravo Y, Munoz P, Castillo J, Ruiz-Alegria C, Sanchez-Velasco P, Leyva-Cobian F, Cid C: Thymidylate synthase promoter tandem repeat and MTHFD1 R653Q polymorphisms modulate the risk for migraine conferred by the MTHFR T677 allele. Molecular Brain Research. 2005, 139 (1): 163-168. 10.1016/j.molbrainres.2005.05.015.View ArticlePubMedGoogle Scholar
- Bottini F, Celle ME, Calevo MG, Amato S, Minniti G, Montaldi L, Di Pasquale D, Cerone R, Veneselli E, Molinari AC: Metabolic and genetic risk factors for migraine in children. Cephalalgia. 2006, 26 (6): 731-737. 10.1111/j.1468-2982.2006.01107.x.View ArticlePubMedGoogle Scholar
- Pezzini A, Grassi M, Del Zotto E, Giossi A, Monastero R, Dalla Volta G, Archetti S, Zavarise P, Camarda C, Gasparotti R, Magoni M, Camarda R, Padovani A: Migraine Mediates the Influence of C677T MTHFR Genotypes on Ischemic Stroke Risk With a Stroke-Subtype Effect. Stroke. 2007, 38 (12): 3145-3151. 10.1161/STROKEAHA.107.491506.View ArticlePubMedGoogle Scholar
- Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD: Homocysteine and stroke: evidence on a causal link from mendelian randomisation. The Lancet. 2005, 365 (9455): 224-232.View ArticleGoogle Scholar
- Alpert JE, Mischoulon D, Nierenberg AA, Fava M: Nutrition and depression: focus on folate. Nutrition. 2000, 16 (7-8): 544-546. 10.1016/S0899-9007(00)00327-0.View ArticlePubMedGoogle Scholar
- Di Rosa G, Attina S, Spano M, Ingegneri G, Sgro DL, Pustorino G, Bonsignore M, Trapani-Lombardo V, Tortorella G: Efficacy of Folic Acid in Children With Migraine, Hyperhomocysteinemia and MTHFR Polymorphisms. Headache: The Journal of Head and Face Pain. 2007, 47 (9): 1342-1344. 10.1111/j.1526-4610.2007.00932.x.View ArticleGoogle Scholar
- Agustin O, Maria T, Natalia V, Jesus C, Ana AA, Yolanda B, Carlos RA, Estrella Q, Julio P: The Relationship Between Homocysteine and Genes of Folate-Related Enzymes in Migraine Patients. Headache: The Journal of Head and Face Pain. 2009, 50 (1): 99-168.Google Scholar
- Joshi G, Pradhan S, Mittal B: Role of the ACE ID and MTHFR C677T polymorphisms in genetic susceptibility of migraine in a north Indian population. Journal of the Neurological Sciences. 2009, 277 (1): 133-137. 10.1016/j.jns.2008.11.002.View ArticlePubMedGoogle Scholar
- de Tommaso M, Difruscolo O, Sardaro M, Losito L, Serpino C, Pietrapertosa A, Santeramo MT, Dicuonzo F, Carella A, Lamberti P, Livrea P: Influence of MTHFR Genotype on Contingent Negative Variation And MRI Abnormalities in Migraine. Headache: The Journal of Head and Face Pain. 2007, 47 (2): 253-265. 10.1111/j.1526-4610.2006.00690.x.View ArticleGoogle Scholar
- Bottini F, Celle M, Calevo M, Amato S, Minniti G, Montaldi L, Pasquale DD, Cerone R, Veneselli E, Molinari A: Metabolic and genetic risk factors for migraine in children. Cephalalgia. 2006, 26 (6): 731-737. 10.1111/j.1468-2982.2006.01107.x.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/66/prepub