MTHFR Ala222Val polymorphism and clinical characteristics confer susceptibility to suicide attempt in chronic patients with schizophrenia

Abstract

Patients with schizophrenia (SCZ) exhibit higher suicide rates than the general population. However, the molecular mechanism responsible for the high rate of suicidal behavior in SCZ remains poorly understood. MTHFR Ala222Val (C677T; rs 1801133) polymorphism has repeatedly demonstrated to play a pathological role in numerous mental disorders, but none of these studies focused on the susceptibility of suicidal behavior in SCZ. In the present cross-sectional study, we recruited 957 chronic inpatients with SCZ and 576 healthy controls to assess the psychopathological symptoms of SCZ and compare the frequency of the MTHFR Ala222Val genotype in both suicide attempters and non-attempters. Our results demonstrated no significant differences in MTHFR Ala222Val genotype and allele distributions between the SCZ patients and controls (p > 0.05), but showed a statistical significance in the distribution of Ala/Val genotype between suicide attempters and nonattempters (p < 0.05). Further logistic regression analysis showed that MTHFR Ala222Val genotype, psychopathological symptoms, number of cigarettes smoked per day and drinking status were related to suicide attempts in SCZ (p < 0.05). Our study demonstrated that MTHFR Ala222Val polymorphism and some clinical characteristics might confer susceptibility to suicide in patients with SCZ. Patients with schizophrenia (SCZ) are at high risk for attempting and completing suicide. Suicide is characterized by intentional termination of one's life, which is an important sequelae of chronic schizophrenia 1,2. To date, suicide has been considered one of the most common causes of premature death in SCZ patients 3. The average life expectancy of patients with SCZ is estimated to have decreased by approximately 14.6 years by suicide 4. However, the pathophysiological mechanisms for the suicidality of SCZ patients are still unclear, particularly the biological pathological mechanism. Evidence from twins, adoption, and family studies showed a significant increase of suicidal rates in suicidal probands 5 , which suggests that genetic risk factors may play an important role in suicidal behavior. The heritability of suicidal behavior is about 45%, while environmental components account for 57% 6. Based on earlier genetic association studies focusing on several biological systems associated with suicidal attempts, a variety of potential candidate genes have been identified. For example, brain-derived neurotrophic factor (BDNF) and its receptor (NTRK2), which are highly expressed in the prefrontal cortex and hippocampus, have been shown as strong candidates for suicide; however, these results are controversial 6. Also, another biological system involved in serotonergic transmission has been found to be candidate genes for suicidal behavior, including a tryptophan hydroxylase involved in synthesis, monoamine oxidase A involved in degradation, and a serotonin-1-A receptor involved in transmission 7. Studies have demonstrated that nearly 90-98% of suicides are committed by people with some type of ...

Early-onset schizophrenia is associated with immune-related rare variants in a Chinese sample

“…CHRM2 also belongs to the muscarinic receptors family, and is involved in acetylcholinergic functions in the central and peripheral nervous system (Brown, 2010). Interestingly, MTHFR (Methylenetetrahydrofolate Reductase) is a gene well-known to be involved in SCZ (El-Hadidy, Abdeen, Abd El-Aziz, & Al-Harrass, 2014; Liu et al, 2020; Peerbooms et al, 2011). A large-scale meta-analysis comprising 2,159 EOS and 6,561 HC found a significant variant, i.e., rs1801133, which is located in the fifth exon of MTHFR (Guo et al, 2021).…”

Genetics and Epigenetics of One-Carbon Metabolism Pathway in Autism Spectrum Disorder: A Sex-Specific Brain Epigenome?

“…Within the folate cycle, the MTHFR enzyme catalyzes the synthesis of the active folate isoform (i.e., 5-methyl-THF) efficiently involved in DNA synthesis and methylation processes [43,51]. MTHFR gene defects and variants have been associated with an array of complex neurological conditions [67,68].…”

“…MTHFR A1298C variant is due to an adenine change in a cytosine at position 1298 of exon 7 leading to the replacement of glutamic acid by an alanine (E429A) resulting in an enzyme with reduced activity more detrimental in the homozygous 1298CC condition though at a lesser extent than the C677T [72,73]. The association of A1298C with NTD and mental illness seems almost controversial [67]. One possible explanation for such diverse findings is that the risk for NTD might depend on the combined gene polymorphisms and/or additional genes and variants also influenced by nutritional factors [69,74].…”

Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase

“…MTHFR dysfunction has been implicated in human diseased states 18 , 19 ranging from cancers 20 to psychiatric illnesses 21 . As such, providing a structural blueprint by which patient mutations in MTHFR can be understood has important implications for human health, and would allow for targeted drug discovery and therapy development.…”