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Differential Metabolites in Chinese Autistic Children: A Multi-Center Study Based on Urinary 1H-NMR Metabolomics Analysis

  • Ma, Yu1
  • Zhou, Hao2
  • Li, Chunpei1
  • Zou, Xiaobing3
  • Luo, Xuerong4
  • Wu, Lijie5
  • Li, Tingyu6
  • Chen, Xiang7
  • Mao, Meng8
  • Huang, Yi9
  • Li, Erzhen10
  • An, Yanpeng11
  • Zhang, Lili1
  • Wang, Tianqi1
  • Xu, Xiu12
  • Yan, Weili13
  • Jiang, Yonghui14
  • Wang, Yi1
  • 1 Department of Neurology, Children's Hospital of Fudan University, Shanghai , (China)
  • 2 Department of Pediatrics, Guizhou Provincial People's Hospital, Guiyang , (China)
  • 3 Child Development Behaviour Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou , (China)
  • 4 Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha , (China)
  • 5 Department of Children and Adolescent Health, School of Public Health, Harbin Medical University, Harbin , (China)
  • 6 Department of Child Health Care, Children's Hospital of Chongqing Medical University, Chongqing , (China)
  • 7 The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou , (China)
  • 8 Department of Child Health Care, Chengdu Women and Children's Hospital, Chengdu , (China)
  • 9 Department of Psychiatry, West China Hospital of Sichuan University, Chengdu , (China)
  • 10 Department of Neurology, Capital Institute of Paediatrics, Beijing , (China)
  • 11 State Key Laboratory of Genetic Engineering, Metabonomics and Systems Biology Laboratory, School of Life Sciences, Fudan University, Shanghai , (China)
  • 12 Department of Child Health Care, Children's Hospital of Fudan University, Shanghai , (China)
  • 13 Department of Clinical Epidemiology, Children's Hospital of Fudan University, Shanghai , (China)
  • 14 Department of Genetics and Paediatrics, Yale School of Medicine, New Haven, CT , (United States)
Published Article
Frontiers in Psychiatry
Frontiers Media SA
Publication Date
May 11, 2021
DOI: 10.3389/fpsyt.2021.624767
  • Psychiatry
  • Original Research


Background: Autism spectrum disorder (ASD) is a group of early-onset neurodevelopmental disorders. However, there is no valuable biomarker for the early diagnosis of ASD. Our large-scale and multi-center study aims to identify metabolic variations between ASD and healthy children and to investigate differential metabolites and associated pathogenic mechanisms. Methods: One hundred and seventeen autistic children and 119 healthy children were recruited from research centers of 7 cities. Urine samples were assayed by 1H-NMR metabolomics analysis to detect metabolic variations. Multivariate statistical analysis, including principal component analysis (PCA), and orthogonal projection to latent structure discriminant analysis (OPLS-DA), as well as univariate analysis were used to assess differential metabolites between the ASD and control groups. The differential metabolites were further analyzed by receiver operating characteristics (ROC) curve analysis and metabolic pathways analysis. Results: Compared with the control group, the ASD group showed higher levels of glycine, guanidinoacetic acid, creatine, hydroxyphenylacetylglycine, phenylacetylglycine, and formate and lower levels of 3-aminoisobutanoic acid, alanine, taurine, creatinine, hypoxanthine, and N-methylnicotinamide. ROC curve showed relatively significant diagnostic values for hypoxanthine [area under the curve (AUC) = 0.657, 95% CI 0.588 to 0.726], creatinine (AUC = 0.639, 95% CI 0.569 to 0.709), creatine (AUC = 0.623, 95% CI 0.552 to 0.694), N-methylnicotinamide (AUC = 0.595, 95% CI 0.523 to 0.668), and guanidinoacetic acid (AUC = 0.574, 95% CI 0.501 to 0.647) in the ASD group. Combining the metabolites creatine, creatinine and hypoxanthine, the AUC of the ROC curve reached 0.720 (95% CI 0.659 to 0.777). Significantly altered metabolite pathways associated with differential metabolites were glycine, serine and threonine metabolism, arginine and proline metabolism, and taurine and hypotaurine metabolism. Conclusions: Urinary amino acid metabolites were significantly altered in children with ASD. Amino acid metabolic pathways might play important roles in the pathogenic mechanisms of ASD.

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