Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Jan 19, 2024; 14(1): 88-101
Published online Jan 19, 2024. doi: 10.5498/wjp.v14.i1.88
Des-Arg(9) bradykinin as a causal metabolite for autism spectrum disorder
Zhong-Yu Huang, Zi-Pan Lyu, Hong-Gui Li, Hua-Zhi You, Xiang-Na Yang, Cai-Hui Cha
Zhong-Yu Huang, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, Guangdong Province, China
Zi-Pan Lyu, School of Biological Sciences, Nanyang Technological University, Nanyang Ave 639798, Singapore
Hong-Gui Li, Department of Pediatrics, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Hua-Zhi You, Department of Nutrition, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Xiang-Na Yang, Department of Pediatric Traditional Chinese Medicine Clinic, Guangzhou Women and Children's Medical Center, Guangzhou 510632, Guangdong Province, China
Cai-Hui Cha, Department of Psychology, Guangzhou Women and Children's Medical Center, Guangzhou 510632, Guangdong Province, China
Co-first authors: Zhong-Yu Huang and Zi-Pan Lyu.
Author contributions: Huang ZY and Lyu ZP contributed toward the concept, data analysis, manuscript writing, manuscript review and funding; Li HG, You HZ, Yang XN and Cha CH contributed toward data collection, data analysis and manuscript review.
Supported by The Guangdong Basic and Applied Basic Research Foundation, No. 2023A1515011432; The Guangzhou Science and Technology Planning Project, No. 2023A04J0627; and National Natural Science Foundation of China, No. 82004256.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Guangzhou First People's Hospital (approval No. S-2022-208).
Informed consent statement: This study was carried out based on publicly available dataset that published by previous researches. Therefore, there’s no informed consent statement.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data used to support the findings of this study are available from the first author (mail:zy1717086@163.com) upon request.
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.
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: Zhong-Yu Huang, MD, PhD, Assistant Professor, Research Fellow, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510000, Guangdong Province, China. zy1717086@163.com
Received: July 31, 2023
Peer-review started: July 31, 2023
First decision: November 1, 2023
Revised: November 8, 2023
Accepted: December 7, 2023
Article in press: December 7, 2023
Published online: January 19, 2024
Processing time: 172 Days and 7.5 Hours
Abstract
BACKGROUND

Early diagnosis and therapeutic interventions can greatly enhance the developmental trajectory of children with autism spectrum disorder (ASD). However, the etiology of ASD is not completely understood. The presence of confounding factors from environment and genetics has increased the difficulty of the identification of diagnostic biomarkers for ASD.

AIM

To estimate and interpret the causal relationship between ASD and metabolite profile, taking into consideration both genetic and environmental influences.

METHODS

A two-sample Mendelian randomization (MR) analysis was conducted using summarized data from large-scale genome-wide association studies (GWAS) including a metabolite GWAS dataset covering 453 metabolites from 7824 European and an ASD GWAS dataset comprising 18381 ASD cases and 27969 healthy controls. Metabolites in plasma were set as exposures with ASD as the main outcome. The causal relationships were estimated using the inverse variant weight (IVW) algorithm. We also performed leave-one-out sensitivity tests to validate the robustness of the results. Based on the drafted metabolites, enrichment analysis was conducted to interpret the association via constructing a protein-protein interaction network with multi-scale evidence from databases including Infinome, SwissTargetPrediction, STRING, and Metascape.

RESULTS

Des-Arg(9)-bradykinin was identified as a causal metabolite that increases the risk of ASD (β = 0.262, SE = 0.064, PIVW = 4.64 × 10-5). The association was robust, with no significant heterogeneity among instrument variables (PMR Egger = 0.663, PIVW = 0.906) and no evidence of pleiotropy (P = 0.949). Neuroinflammation and the response to stimulus were suggested as potential biological processes mediating the association between Des-Arg(9) bradykinin and ASD.

CONCLUSION

Through the application of MR, this study provides practical insights into the potential causal association between plasma metabolites and ASD. These findings offer perspectives for the discovery of diagnostic or predictive biomarkers to support clinical practice in treating ASD.

Keywords: Des-Arg(9) bradykinin; Autism spectrum disorder; Mendelian randomization; Metabolite; Enrichment analysis

Core Tip: This study employs Mendelian randomization to uncover a potential causal relationship between plasma metabolites and autism spectrum disorder (ASD), emphasizing the role of Des-Arg(9)-bradykinin in increasing the risk of ASD. The findings underscore the significance of neuroinflammation and the response to stimulus as possible mediating factors, offering new directions for the development of diagnostic and predictive biomarkers in the clinical management of ASD.