title: Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression.
abstract: Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc 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 MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L 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 MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-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 MTHFD1L is responsible for increased rumination or other long-term effects on brain development.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: N
authors.initials: N
authors.lastname: Eszlari
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Kovacs
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: P
authors.initials: P
authors.lastname: Petschner
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Pap
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.|Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary.
authors.forename: X
authors.initials: X
authors.lastname: Gonda
authors.affiliation: Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK.|Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: R
authors.initials: R
authors.lastname: Elliott
authors.affiliation: Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK.|Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: I M
authors.initials: IM
authors.lastname: Anderson
authors.affiliation: Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK.|Manchester Academic Health Sciences Centre, Manchester, UK.|Manchester Mental Health and Social Care Trust, Manchester, UK.
authors.forename: J F W
authors.initials: JF
authors.lastname: Deakin
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Bagdy
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.|Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK.|Manchester Academic Health Sciences Centre, Manchester, UK.|MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Juhasz
mesh_terms: D000328:Adult; D000619:Aminohydrolases / Q000235:genetics*; D003072:Cognition Disorders / Q000150:complications* / Q000235:genetics*; D003866:Depressive Disorder / Q000150:complications* / Q000235:genetics*; D005260:Female; D005492:Folic Acid; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics*; D006801:Humans; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009097:Multienzyme Complexes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D009097:Multienzyme Complexes; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase