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The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis


Low dietary folate intake has been implicated as a risk factor for depression. However, observational epidemiological studies are plagued by problems of confounding, reverse causality and measurement error. A common polymorphism (C677T) in MTHFR is associated with methyltetrahydrofolate reductase (MTHFR) activity and circulating folate and homocysteine levels and offers insights into whether the association between low folate and depression is causal. We genotyped this polymorphism in 3478 women in the British Women's Heart and Health Study. In these women, we looked at the association between genotype and three indicators of depression; ever diagnosed as depressed, currently taking antidepressants and the EuroQol mood question. We also carried out a systematic review and meta-analysis of all published studies which have looked at the association between MTHFR C677T genotype and depression. In the British Women's Heart and Health Study, we found evidence of an increased risk of ever being diagnosed as depressed in MTHFR C677T TT individuals compared with CC individuals, odds ratio (OR) 1.35(95% CI: 1.01, 1.80). Furthermore, we identified eight other studies, which have examined the association between depression and MTHFR C677T. We were able to include all of these studies in our meta-analysis together with our results, obtaining an overall summary OR of 1.36 (95% CI: 1.11, 1.67, P=0.003). Since this genotype influences the functioning of the folate metabolic pathway, these findings suggest that folate or its derivatives may be causally related to risk of depression.

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The British Women's Heart and Health Study is co-directed by Professor Shah Ebrahim, Dr Debbie Lawlor, Professor Peter Whincup and Dr Goya Wannamethee. We thank Carol Bedford, Alison Emerton, Nicola Frecknall, Karen Jones, Rita Patel, Mark Taylor and Katherine Wornell for collecting and entering data, all of the general practitioners and their staff who have supported data collection, and the women who have participated in the study. We also thank Professor Ian Hickie, Dr Sharon Naismith and Professor Osvaldo Almeida who provided data from their studies for the meta-analysis. The British Women's Heart and Health Study is funded by the UK Department of Health and the British Heart Foundation. DAL is funded by a UK Department of Health Career Scientist Award. NT is funded by a UK Medical Research Council studentship. The views expressed in this publication are those of the authors and not necessarily those of any of the funding bodies. The funding bodies have had no influence over the scientific work or its publication.

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Correspondence to S J Lewis.

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SJL undertook the literature review, carried out the meta-analysis and coordinated the writing of the paper. DAL is a co-director of the BWHHS, carried out the analysis using the BWHHS data and contributed to the interpretation of the analysis. GDS contributed to the study design and conduct, and to the interpretation of the analysis. RA provided advice on the interpretation of depression outcomes. NT and INMD coordinated the genotyping and DNA extraction. SE is the principle investigator of the BWHHS and contributed to the interpretation of the analysis. All authors contributed to the final version of this paper.

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Lewis, S., Lawlor, D., Davey Smith, G. et al. The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis. Mol Psychiatry 11, 352–360 (2006).

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  • depression
  • polymorphism
  • folate
  • genetic

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