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.
Highlights
Major depressive disorder is an etiologically heterogeneous condition,[1] in which a core and specific feature is depressive rumination.[2]Ruminative response style, which is sometimes referred as depressive rumination, can be defined in several ways.[3]
It is a form of cognitive inflexibility or perseverative cognition that prolongs the negative effect of everyday life stressors.[4,5]
Among polymorphisms of folate pathway genes, the widely investigated methylenetetrahydrofolate reductase (MTHFR) rs1801133 is not associated with ruminative response style in our large combined European white sample, whereas the Alzheimer’s disease (AD) genome-wide marker MTHFD1L rs11754661 A allele represents a risk for higher ruminative response style
Summary
Major depressive disorder is an etiologically heterogeneous condition,[1] in which a core and specific feature is depressive rumination.[2]. The A allele, similar to the MTHFR 677 T allele, is associated with increased homocysteine concentrations.[30] This enzyme is obligatory for the production of mitochondrial formate, the essential substrate for cytoplasmic purine and thymidylate biosynthesis, methionine biosynthesis and amino-acid metabolism.[29,31]. The direct link between rumination and AD is as yet only hypothetical,[32] the association of the MTHFD1L gene with age-related cognitive decline, together with its pivotal role in normal neuronal development,[31,33,34] suggests that it could be relevant in cognitive processes throughout the life. We investigated the association of ruminative response style with MTHFR rs1801133 and MTHFD1L rs11754661. We investigated the significant effects separately in the Budapest and Manchester samples to test possible replications. We examined the relationship between folate pathway genes, rumination and depression phenotypes.
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