This study used blood metabolomics and MR of preschool enrolled in cohort studies to assess the association between serum metabolites and childhood-diagnosed ADHD. A total of 112 differentiated metabolites were identified in the metabolomics results of the cohort study, with 69 metabolites showing upregulation and 43 metabolites showing downregulation. Fifteen genetically determined metabolites were found to be causally associated with childhood-diagnosed ADHD using more rigorous MR analysis criteria, with arginine and α-tocopherols overlapping with metabolomic differential metabolites in cohort studies. In addition, pathway enrichment analysis identified two important metabolic pathways, the "Biliary secretion" pathway and the "metabolic pathways of arginine and proline" pathway.
According to previous findings, this is the first study of childhood-diagnosed ADHD that combines cohort studies, MR studies, and metabolomics. Here, the results identified a cluster of metabolites in serum associated with childhood-diagnosed ADHD, with Alpha-tocopherol having a potent effect on childhood-diagnosed ADHD. In a recent study, it was elucidated that alpha-tocopherol has a positive effect as a non-enzymatic antioxidant against depression and anxiety (26–28). Several studies have shown that alpha-tocopherol antioxidant supplementation therapy can effectively enhance the oxidative defense function of the body (29–31). Also, a case-control study suggested that mild oxidative stress and immune disorders may affect ADHD (32). Thus α-tocopherol may play an important role in the neurodevelopment of childhood-diagnosed ADHD.
This joint conjoint analysis also identified arginine (Arg) as an important genetically determined essential metabolite both inside and outside the RI. Arginine is a semi-essential amino acid and the Arg pathway is associated with cardiovascular, renal, neurological, and immune system disorders (33, 34). the Arg pathway is significantly different in pediatric patients with congenital metabolic disorders, type I diabetes, or ADHD matched to healthy age (35–39), and it is worth mentioning that our results are in agreement with the above results, emphasizing the importance of arginine in the progression of mental disorders.
In this study, metabolic pathway analysis showed that the "primary bile acid biosynthesis" and "Arginine and proline metabolism" pathways were primarily associated with childhood-diagnosed ADHD. The study found that primary bile acids are not associated with ADHD. It was found that primary bile acid metabolites/pathways are involved in metabolic functions related to brain health and play an important role in several psychiatric disorders: depression and anxiety disorders, and these results are consistent with those of the present study (40–43). Similarly, the arginine and proline metabolic pathways are involved in the progression of diseases such as irritable bowel syndrome and amyotrophic lateral sclerosis (44, 45). In conclusion, it is likely that these two important metabolic pathways play an important role in childhood-diagnosed ADHD.
Of course, our study has some limitations. The small sample size of our cohort study is to be followed up by continued sample collection and enrollment for validation of a large sample. Of course, we are already working on the inclusion of cohort members in a large sample and are also focusing on whether changes in the participants' gut flora metabolites are related to serum metabolites. In addition, the questionnaires for ADHD in this cohort were sourced from their guardians, and the presence of information bias cannot be excluded. Also, the accuracy of the MR analysis depends on the interpretation of the instrumental variables of exposure. Further expanded sample sizes and multiple pedigree studies that are not limited to individuals of European ancestry may more accurately assess genetic effects on metabolites.