Zhang CY, Chen YL, Hou F, Li YZ, Wang WX, Guo L, Zhang CX, Li L, Lu CY. Association of folate metabolism gene polymorphisms with autism susceptibility and symptom severity in the Chinese population. World J Psychiatry 2025; 15(10): 108776 [DOI: 10.5498/wjp.v15.i10.108776]
Corresponding Author of This Article
Ci-Yong Lu, MD, PhD, Professor, Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China. luciyong@mail.sysu.edu.cn
Research Domain of This Article
Genetics & Heredity
Article-Type of This Article
Case Control Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Cai-Yun Zhang, Yan-Zhi Li, Wan-Xin Wang, Lan Guo, Cai-Xia Zhang, Ci-Yong Lu, Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
Yan-Lin Chen, Fang Hou, Li Li, Department of Child Health Care, Maternity and Children Health Care Hospital of Luohu District, Shenzhen 518019, Guangdong Province, China
Author contributions: Zhang CY conducted the research, performed statistical analyses, and wrote the manuscript; Zhang CY and Chen YL contributed equally to this article, they are the co-first authors of this manuscript; Zhang CY, Chen YL, and Li L collected data; Chen YL, Hou F, Li YZ, Wang WX, Guo L, Zhang CX, and Lu CY assisted with data analysis and revised the manuscript; Hou F, Li YZ, Wang WX, Guo L, and Zhang CX contributed to data interpretation; Li L was responsible for facilitating clinical data access, overseeing patient recruitment, and providing critical revisions to the manuscript; Lu CY supervised the overall study design; Li L and Lu CY contributed equally to this article, they are the co-first authors of this manuscript; and all authors have read and approved the final version of the manuscript.
Supported by the National Key Research and Development Program of China, No. 2024YFC2707801; and the Science and Technology Innovation Commission of Shenzhen, No. JCYJ20230807143800002.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Shenzhen Luohu Maternal and Child Health Hospital, approval No. LL20230801061.
Informed consent statement: Informed consent was obtained from the parents or legal guardians of all participants.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The datasets used and/or analyzed in the present study can be obtained from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ci-Yong Lu, MD, PhD, Professor, Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China. luciyong@mail.sysu.edu.cn
Received: April 23, 2025 Revised: June 4, 2025 Accepted: July 18, 2025 Published online: October 19, 2025 Processing time: 156 Days and 18.2 Hours
Abstract
BACKGROUND
Folate metabolism gene polymorphisms may play an important role in the pathogenesis of autism spectrum disorder (ASD). However, most studies have primarily used single candidate gene typing strategies (such as targeted polymerase chain reaction technology), and current findings remain inconsistent.
AIM
To investigate the association of folate metabolism gene polymorphisms with ASD susceptibility and symptom severity among Chinese children.
METHODS
Whole-exome sequencing (WES) was conducted to systematically screen for coding region variants of key genes in the folate metabolism pathway among children with ASD, focusing on identifying polymorphisms with high mutation frequencies and potential pathogenic effects. A case-control study was then conducted to explore the association of candidate folate metabolism gene polymorphisms with the susceptibility and severity of ASD.
RESULTS
WES was performed on 70 children with ASD, and the case-control study included 170 children with ASD and 170 healthy controls. WES revealed that 84.3% (59/70) of children with ASD carried potentially pathogenic variants enriched in folate metabolism pathways. MTHFR C677T and MTRR A66G were significantly associated with an increased risk of ASD in both codominant and dominant models (P < 0.05). The dominant model of MTRR A66G was also significantly associated with higher scores in the domains of social relations, body and object use, social and adaptive skills, total scores on the Autism Behavior Checklist, as well as emotional reactivity, nonverbal communication, and activity level on the Childhood Autism Rating Scale (P < 0.05).
CONCLUSION
Most children with ASD carry deleterious variants in folate metabolism-related pathways. MTHFR C677T and MTRR A66G mutations are significantly associated with ASD.
Core Tip: This study screened high-frequency and potentially deleterious polymorphisms in folate metabolism-related genes among children with autism spectrum disorder (ASD) using whole-exome sequencing and explored their associations with ASD through a case-control study. The study found that specific folate metabolism gene polymorphisms were significantly associated with both ASD susceptibility and symptom severity. These findings highlight the critical role of the folate metabolism pathway in the pathogenesis of ASD and provide potential molecular targets for early risk assessment and personalized nutritional intervention strategies.
Citation: Zhang CY, Chen YL, Hou F, Li YZ, Wang WX, Guo L, Zhang CX, Li L, Lu CY. Association of folate metabolism gene polymorphisms with autism susceptibility and symptom severity in the Chinese population. World J Psychiatry 2025; 15(10): 108776
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social communication, restricted interests, and repetitive behaviors[1]. The prevalence of ASD has steadily increased worldwide, with approximately 1 in 54 children diagnosed[2,3]. As one of the fastest-growing developmental disorders, ASD has emerged as the leading cause of disability among children with neuropsychiatric disorders, posing a substantial public health challenge that markedly impairs quality of life[4]. There, it is urgent to elucidate modifiable risk factors and pathophysiological mechanisms of ASD.
Emerging studies suggest that genetic polymorphisms in the folate metabolism pathway may play an important role in the pathogenesis of ASD[5-8]. Folate metabolism supports essential biochemical and neurodevelopmental processes through its roles in methylation, homocysteine regulation, and redox-immune balance[9-13]. Folate metabolism is a complex biochemical process involving the coordinated action of multiple key enzymes and transporters[14]. Deleterious mutations in the coding regions of genes encoding these enzymes or transporters may alter enzyme activity or protein function, thereby disrupting folate metabolism and increasing the susceptibility of ASD[13,15]. Moreover, recent evidence suggests that folate metabolism gene polymorphisms are associated with the therapeutic efficacy of folinic acid for individuals with ASD[16].
Current research has primarily focused on the association between MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G polymorphisms and ASD susceptibility[17,18]. However, findings across studies remain inconsistent, and no clear consensus has been established, particularly in the Chinese population[18]. Moreover, there are ethnic differences in the allele frequencies of folate metabolism gene polymorphisms, and the Chinese population remains underrepresented in ASD research[19]. Furthermore, most existing studies employ candidate genotyping strategies [e.g., targeted polymerase chain reaction (PCR) technology] that typically focus on a single candidate locus for typing (e.g., MTHFR C677T). This narrow scope limits the ability to comprehensively identify pathogenic variants across the entire coding region, potentially overlooking deleterious mutations that may play a critical role in ASD susceptibility. Studies have shown that approximately 90% of disease-causing mutations are located in the exon regions (i.e., protein-coding region)[20,21]. Thus, whole-exome sequencing (WES) has emerged as a powerful tool for uncovering genetic variation associated with ASD than traditional genotyping methods[20,21].
Therefore, this study aimed to investigate the association of folate metabolism gene polymorphisms with autism susceptibility and symptom severity among Chinese children. First, WES was conducted to systematically screen for coding region variants of key genes in the folate metabolism pathway among ASD patients, focusing on identifying polymorphisms with high mutation frequencies and potential pathogenic effects. Second, a case-control study was conducted to explore the association between candidate folate metabolism gene polymorphisms and ASD susceptibility. Lastly, this study explored the relationship between folate metabolism gene polymorphisms and the severity of clinical symptoms of ASD. The findings may enhance our understanding of the genetic mechanisms underlying ASD and provide potential targets for personalized nutritional interventions in this population.
MATERIALS AND METHODS
Participants
This study recruited children aged 3 years to 6 years between August 2023 and March 2025 and classified them into an ASD group and a typically developing control group. The ASD group consisted of children who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria and were independently diagnosed by two professional clinicians. Children with ASD were recruited from three hospitals in Shenzhen that specialize in the rehabilitation of neurodevelopmental disorders: Luohu District Maternal and Child Health Hospital, Luohu District Traditional Chinese Medicine Hospital, and Guangsheng Hospital. ASD children were excluded if they were diagnosed with Rett syndrome, fragile X syndrome, congenital heart disease, hepatic or renal dysfunction, epilepsy, structural brain abnormalities, mitochondrial disorders, or other inherited metabolic diseases. Children in the control group were recruited from public kindergartens in the Luohu District, Shenzhen. Control participants were confirmed to be free of physical illnesses, neurodevelopmental or psychiatric disorders, and ASD symptoms based on physical examinations and developmental screening. A detailed flowchart of the study is shown in Figure 1.
Figure 1 The flowchart of this study.
ASD: Autism spectrum disorder.
Assessment of autism symptom severity
The Autism Behavior Checklist (ABC) consisted of 57 items and is widely used in clinical practice for its simplicity, ease of use, strong operability, and high reliability and validity[22,23]. It comprises five subscales: Sensory behavior, social relating, body and object use, language and communication skills, and social and adaptive skills. The total score is 158, with higher scores indicating more severe ASD symptoms. Parents or guardians completed the checklist based on their child’s behaviors over the past month. The scale’s internal consistency, as measured by Cronbach’s α coefficient, was 0.95.
The Childhood Autism Rating Scale (CARS) is widely used in clinical practice for its strong reliability and validity[24]. The CARS comprises 15 items that assess multiple aspects, such as imitation, verbal communication, and nonverbal communication[25]. Each item is rated on a four-point scale, ranging from “normal performance consistent with age” to “severe abnormality”. Cronbach’s α coefficient for this scale was 0.92.
WES and screening of deleterious variants
Genomic DNA was extracted from the peripheral blood of children with ASD. The WES data analysis pipeline was designed based on the best practice workflow recommended by the Genome Analysis ToolKit of the Broad Institute[26]. The specific process included the following main steps: Library capture, library quality control, on-machine sequencing, sample data quality control, sequence alignment, variant detection, and functional annotation. The eMethods in the Supplementary material provided detailed methods for WES detection and screening of deleterious variants.
Pathway enrichment analysis
After screening for potential pathogenic variant sites, pathway enrichment analysis was performed on the genes with harmful mutations in each child with ASD on an individual basis, and the number of children with ASD enriched in the same pathway was counted. Pathway enrichment analysis was conducted using the online bioinformatics platform DAVID (https://david-d.ncifcrf.gov). Based on the Kyoto Encyclopedia of Genes and Genomes database, the enrichment of candidate genes in classical signaling and metabolic pathways was analyzed[27].
Genotyping
MTHFR C677T (Ala222Val, rs1801133), MTRR A66G (Ile22Met, rs1801394), and BHMT G716A (Arg239Gln, rs3733890)[15,28] were genotyped using the gold standard method of PCR and Sanger sequencing[29]. The eMethods in the Supplementary material provided detailed methods for genotyping. The primer sequences and PCR product lengths for genotyping folate metabolism gene polymorphisms are provided in Supplementary Table 1.
Statistical analysis
Categorical variables were presented as frequencies and percentages, whereas continuous variables were expressed as means with standard deviations. Between-group comparisons were conducted using the χ2 test for categorical variables and the t-test for continuous variables. When cell sizes were small or the assumptions for the χ2 test were not met, Fisher’s exact test was used. Hardy-Weinberg equilibrium of genotype frequencies for folate metabolism gene polymorphism was assessed using the χ2 test[30].
A χ2 test was performed to compare the genotype frequencies of folate metabolism gene polymorphism between the ASD and control groups. The logistic regression model was used to analyze the associations with ASD susceptibility in the codominant (XX vs YY; XY vs YY), dominant (XX + XY vs YY), and recessive (XX vs XY + YY) models[31,32]. For folate metabolism gene polymorphisms were significantly associated with ASD susceptibility, the linear regression model was used to investigate associations with symptom severity. Both logistic and linear regression analyses generated two models: Model 1 was unadjusted, and model 2 was adjusted for age, gender, ethnicity, parental age at birth, parental education level, mode of delivery, birthweight, and premature. All statistical analyses were performed using R (version 4.4.1), with P-values less than 0.05 considered statistically significant.
RESULTS
Characteristics
A total of 410 participants were included in this study, comprising 240 children diagnosed with ASD and 170 typically developing controls (Table 1). WES was performed on 70 children with ASD, including 51 boys (72.9%) and 19 girls (27.1%). No statistically significant gender differences were observed in terms of age, ethnicity, parental age at birth, parental education level, mode of delivery, birthweight, and premature (all P > 0.05). In the case-control study, there were 170 participants each in the ASD and control groups. No significant differences were observed between the groups in age, gender, ethnicity, parental age at birth, parental education level, mode of delivery, birthweight, and premature (all P > 0.05).
Table 1 Demographic characteristics of participants (n = 410), n (%).
WES quality metrics and summary statistics are presented in Supplementary Table 2. Sequencing quality metrics indicated high-quality data across all samples, with 98.6% of the bases having a coverage depth ≥ 10 ×. Enrichment analysis showed that the deleterious variants in 45 children with ASD were enriched in the folate-mediated one-carbon metabolism pathway (hsa00670), 39 in the folate transport and metabolism pathway (hsa04981), and 22 in the cysteine and methionine metabolism pathway (hsa00270). Notably, deleterious variants in 14 children with ASD did not overlap with any of these three pathways. Overall, a total of 59 (84.3%) children with ASD carried deleterious variants in folate metabolism-related pathways (Supplementary Table 3). Only variants with assigned reference single nucleotide polymorphism IDs (single nucleotide polymorphism, rs numbers) were retained for further analysis. A total of 28 polymorphic loci spanning 13 genes were ultimately identified and most of which were missense mutations (Supplementary Table 4).
Among all folate metabolism gene polymorphisms, the MTHFR C677T (rs1801133), MTRR A66G (rs1801394), and BHMT G716A (rs3733890) variants exhibited relatively high mutation frequencies of 0.486, 0.486, and 0.543, respectively. Combined Annotation Dependent Depletion scores for these three variants were 25.0, 23.3, and 21.8, respectively (Supplementary Table 5). Therefore, MTHFR C677T, MTRR A66G, and BHMT G716A were prioritized as key candidate gene polymorphisms.
Association between folate metabolism gene polymorphisms and ASD susceptibility
The genotype distributions of the three folate metabolism polymorphisms were consistent with the Hardy-Weinberg equilibrium (P > 0.05) (Supplementary Table 6). There were significant differences in the frequencies of MTHFR C677T and MTRR A66G genotypes between the ASD and control groups (Supplementary Table 7). However, the distribution of the BHMT G716A genotype was not significantly different between the two groups (P = 0.809).
As shown in Table 2, after adjusting for potential confounders (model 2), the codominant model [CT vs CC, adjusted odds ratio (AOR) = 2.38; confidence interval (CI): 1.46-3.92; P < 0.001] and dominant model (TT + CT vs CC, AOR = 2.28; 95%CI: 1.44-3.65; P < 0.001) of MTHFR C677T were significantly associated with ASD susceptibility. Similarly, the codominant model (AG vs AA, AOR = 1.79, 95%CI: 1.12-2.89; P = 0.016) and dominant model (GG +AG vs AA, AOR = 1.74, 95%CI: 1.11-2.73; P = 0.016) of MTRR A66G were also significantly associated with ASD susceptibility. In contrast, the BHMT G716A showed no significant association with ASD susceptibility under any genetic models (P > 0.05).
Table 2 Association between the genetic model of folate metabolism gene polymorphism and autism spectrum disorder susceptibility.
Association between folate metabolism gene polymorphisms and autism symptom severity
As shown in Table 3, the dominant model (GG +AG vs AA) of MTRR A66G was significantly associated with higher scores in the domains of social relating (β = 2.27, 95%CI: 0.73-3.81; P = 0.004), body and object use (β = 2.48, 95%CI: 0.73-4.23; P = 0.006), social and adaptive skills (β = 1.80, 95%CI: 0.60-3.00; P = 0.003), as well as the total ABC score (β = 7.24, 95%CI: 2.37-12.12; P = 0.004). In Table 4, the dominant model (GG + AG vs AA) of MTRR A66G was also significantly associated with higher scores in emotional response (β = 0.21, 95%CI: 0.03-0.39; P = 0.021), nonverbal communication (β = 0.20, 95%CI: 0.03-0.36; P = 0.019), and activity level (β = 0.13, 95%CI: 0.01-0.24; P = 0.031). No significant association was found between MTHFR C677T and ABC or CARS scores (P > 0.05).
Table 3 Association between folate metabolism gene polymorphism and Autism Behavior Checklist.
This study found that 84.3% of children with ASD carried deleterious variants in folate metabolism-related pathways by WES. MTHFR C677T and MTRR A66G were significantly associated with ASD susceptibility in both co-dominant and dominant models. These findings are consistent with previous studies and further support the potential role of folate metabolism gene polymorphisms in ASD pathogenesis[19,34,35]. For example, a case-control study conducted among the Han Chinese population reported a significantly higher frequency of the MTHFR C677T variant in the ASD group (54.5%) than in the control group (28.0%)[19]. Another case-control study also observed a significant association between MTHFR C677T and ASD[34]. Moreover, case-control studies in different ethnic groups from Iraq, India, and Iran have found that MTRR A66G is significantly associated with ASD susceptibility[17,36,37]. MTHFR C677T and MTRR A66G polymorphisms may impair enzyme activity, disrupt normal folate metabolism, elevate homocysteine levels, alter DNA methylation patterns, and affect neurotransmitter balance, thereby increasing vulnerability to ASD[13,14]. However, a case-control study in the Han Chinese population did not observe a significant association between either MTHFR C677T or MTRR A66G and ASD risk or symptom severity[18]. These inconsistent findings may result from methodological differences in sample size, ethnicity, genotyping techniques, and statistical analysis methods[17]. Moreover, environmental factors, such as dietary folate intake, may influence the phenotypic expression of genetic polymorphisms[38]. For example, a meta-analysis revealed that perinatal folate supplementation may reduce the risk of ASD in individuals carrying the MTHFR C677T polymorphism[38].
This study also found that the MTRR A66G variant (AG/GG genotype) was significantly associated with increased clinical severity of ASD. Children carrying the variant exhibited higher symptom scores across multiple domains of the ABC and CARS. However, no significant association was found between MTHFR C677T and ASD symptom severity in this study. This is consistent with findings from a previous study in a Han Chinese population, which reported no significant correlation between MTHFR C677T and ASD symptom severity[18]. This may relate to the different roles of MTHFR and MTRR in the folate metabolic pathway. MTHFR primarily catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thereby providing the necessary methyl donor for homocysteine re-methylation[39]. However, the downstream efficiency of this pathway also relies heavily on MTRR and methionine synthase activity, which may have more direct effects on methylation-dependent neurodevelopmental processes and thus on the severity of autism symptoms[40]. Moreover, the phenotypic effect of MTHFR C677T appears more susceptible to environmental factors[41,42]. When individuals consume adequate folate, the effect of carrying the MTHFR C677T variant may be partially offset by nutritional compensation, which may explain why its association with clinical symptom severity was not reflected in this study[38]. Finally, ASD is highly clinically and genetically heterogeneous, and the phenotypic effects of gene variants may differ between different subgroups of the population.
Although no significant association was observed between BHMT G716A and ASD susceptibility in this study, the key role of BHMT in folate-independent methylation suggests it warrants further investigation. BHMT encodes betaine-homocysteine methyltransferase, which catalyzes the conversion of homocysteine to methionine by betaine, thereby contributing to methyl donor homeostasis. Current evidence does not clearly establish a direct association between BHMT polymorphism and ASD, some studies suggest it may play a role in neurodevelopmental abnormalities[43,44]. For example, in the northern Han Chinese population, the A allele of BHMT G716A was associated with increased risk of neural tube defects[43]. Moreover, experimental evidence from an autism mouse model induced by prenatal valproic acid exposure showed that significantly elevated serum homocysteine levels and reduced BHMT enzyme activity[44].
This study has several strengths. First, high-frequency and potentially deleterious polymorphisms in folate metabolism-related genes were identified through WES, and further explored their association with both ASD susceptibility and symptom severity using a case-control design. Second, individualized pathway enrichment analysis of genes with deleterious mutations in each child with ASD revealed the convergent genetic mechanism underlying ASD. Third, the case-control study employed the gold standard method for genotyping the folate metabolism gene polymorphisms, ensuring high reliability and accuracy. Despite these strengths, several limitations should be acknowledged. First, the case-control study primarily focused on folate metabolism gene polymorphism sites with high mutation frequencies and predicted pathogenicity identified through WES, while other sites with low mutation frequencies were not explored. Future studies should explore the association between these sites and ASD. Second, this study assessed ASD symptom severity using the ABC and CARS. Although both tools are widely used in clinical practice, they are subjective and may introduce measurement bias. Future research should incorporate objective indicators, such as neuroimaging and biomarker testing, to improve the accuracy and clinical applicability of findings.
CONCLUSION
This study found that most children with ASD carried deleterious variants in folate metabolism-related pathways. MTHFR C677T and MTRR A66G mutations were significantly associated with ASD. These findings further support the critical role of the folate metabolic pathway in ASD pathogenesis and highlight potential therapeutic targets for personalized nutritional intervention.
ACKNOWLEDGEMENTS
The authors extend their heartfelt gratitude to all the children and their families for their invaluable participation and commitment to this study.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Psychiatry
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade A
Novelty: Grade A, Grade A
Creativity or Innovation: Grade A, Grade B
Scientific Significance: Grade A, Grade A
P-Reviewer: Biswas MS S-Editor: Bai Y L-Editor: A P-Editor: Zhang XD
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