Roles of 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphisms in First-Episode, Drug-Naive Adult Patients With Depression.

Zhuoqing Li,Jian Xu,Yuqi Cheng,Cong Zhou,Bo He,Nan Dai,Xiufeng Xu,Liangliang Ping,Zonglin Shen

doi:10.3389/fpsyt.2020.531959

Abstract

5,10-Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is considered as a predisposition and promising genetic candidate to major depressive disorder (MDD), as it is associated with impaired one-carbon cycles, which may be involved in the pathogenesis of depression. Cortical thickness (CT) and subcortical structure volumes have been extensively studied in MDD and have been proposed as one of the phenotypes for MDD. We intend to discuss the association between CT, subcortical structure volume, and MTHFR C677T polymorphism in first-episode, treatment-naive patients with MDD. In this study, 127 adult patients with MDD and 101 age- and gender-matched healthy controls (HCs) were included. All subjects underwent T1-weighted MRI, MTHFR C677T genotyping, and FreeSurfer software-based morphological analysis. MDD patients have been detected to have significantly decreased volumes in the left nucleus accumbens (P < 0.001). The MTHFR 677 T allele carriers manifested with thinner CT in the left caudal anterior cingulate cortex (cACC, P = 0.009) compared with CC genotype. There were significant genotype-by-diagnosis interactions for the CT in the left cACC (P = 0.009), isthmus cingulate (P = 0.002), medial orbitofrontal lobe (P = 0.012), posterior cingulate (P = 0.030), and the right lateral orbitofrontal lobe (P = 0.012). We also found a trend in the interaction effect on the volume of the left putamen (P = 0.050). Our results revealed that MTHFR C677T polymorphism may be involved in the dysfunction of limbic–cortical–striatal–pallidal–thalamic (LCSPT) circuits mediating emotion processing, which may contribute to pathogenesis of MDD.

Highlights

Major depressive disorder (MDD) is a chronic persistent complex mental disorder with high morbidity
This study firstly investigated the role of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T in pathophysiological processes of MDD in the Han Chinese population in southern China
Their findings suggested that anhedonia was associated with reduced reward stimuli in nucleus accumbens (NAC) during task fMRI, decreased volume in NAC, and increased rest-state fMRI activity in cACC, which are involved in positive experience-related brain areas

Summary

Introduction

Major depressive disorder (MDD) is a chronic persistent complex mental disorder with high morbidity. Current evidence has indicated that MDD is mainly the outcome of the genetic and environment interactions, such as adverse experiences in childhood, especially childhood maltreatment [1]. MTHFR critically catalyzes the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine (Hcy) remethylation to methionine, which is activated as S-adenosyl methionine (SAM). Defects in the MTHFR enzyme can cause methionine synthesis obstacles for Hcy. The synthesis of SAM from methionine in the organism decreases, and the methylation reaction decreases. High Hcy levels, through triggering the N-methyl-D-aspartate receptor [10], lead to monoamine neurotransmitter synthesis being blocked and essential amino acid levels being reduced in the brain tissue, especially neurotransmitters implicated in depression (such as serotonin, norepinephrine, glutamate, and γ-aminobutyric acid)

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