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In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, <jats:italic>MTHFR<\/jats:italic> rs1801133 (C677T) and <jats:italic>MTHFD1L<\/jats:italic> rs11754661, in a combined European white sample from Budapest, Hungary (<jats:italic>n<\/jats:italic>=895) and Manchester, United Kingdom (<jats:italic>n<\/jats:italic>=1309). <jats:italic>Post hoc<\/jats:italic> analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the <jats:italic>MTHFR<\/jats:italic> rs1801133 showed no effect on rumination. However, the A allele of <jats:italic>MTHFD1L<\/jats:italic> rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of <jats:italic>MTHFD1L<\/jats:italic> rs11754661 on depression phenotypes. These findings suggest that the <jats:italic>MTHFD1L<\/jats:italic> gene, and thus the C<jats:sub>1<\/jats:sub>-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of <jats:italic>MTHFD1L<\/jats:italic> is responsible for increased rumination or other long-term effects on brain development.<\/jats:p>","DOI":"10.1038\/tp.2016.19","type":"journal-article","created":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T15:34:40Z","timestamp":1456846480000},"page":"e745-e745","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression"],"prefix":"10.1038","volume":"6","author":[{"given":"N","family":"Eszlari","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Kovacs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Petschner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Pap","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X","family":"Gonda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I M","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J F W","family":"Deakin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Bagdy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Juhasz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,3,1]]},"reference":[{"key":"BFtp201619_CR1","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.neuron.2014.01.027","volume":"81","author":"J Flint","year":"2014","unstructured":"Flint J, Kendler KS . 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IMA has received consultancy fees from Servier, Alkermes, Lundbeck\/Otsuka and Janssen, an honorarium for speaking from Lundbeck and grant support from Servier and AstraZeneca. RE has received consultancy fees from Cambridge Cognition and P1vital. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}