Association of folate metabolism gene polymorphisms with autism susceptibility and symptom severity in the Chinese population

doi:10.5498/wjp.v15.i10.108776

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Oct 19, 2025 (publication date) through Sep 29, 2025

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World Journal of Psychiatry

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2220-3206

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World J Psychiatry. Oct 19, 2025; 15(10): 108776
Published online Oct 19, 2025. doi: 10.5498/wjp.v15.i10.108776

Association of folate metabolism gene polymorphisms with autism susceptibility and symptom severity in the Chinese population

Cai-Yun Zhang, Yan-Lin Chen, Fang Hou, Yan-Zhi Li, Wan-Xin Wang, Lan Guo, Cai-Xia Zhang, Li Li, Ci-Yong Lu

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

Co-first authors: Cai-Yun Zhang and Yan-Lin Chen.

Co-corresponding authors: Li Li and Ci-Yong Lu.

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.

Keywords: Autism spectrum disorder; Folate metabolism; Gene polymorphism; Susceptibility; Severity

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.