Exploring Causal Associations Between Plasma Metabolites and Autism Spectrum Disorder

Background: In autism spectrum disorder (ASD), the human plasma metabolome is altered but the causal relationship between the levels of metabolites and ASD is unclear. We aimed to assess bidirectional causal associations between plasma metabolites and ASD. Methods: We investigated potential causal associations between the genetic variation contributing to the levels of metabolites and ASD via Mendelian randomization (MR) analyses. Genome-wide association study (GWAS) summary datasets were used in the study, including ASD (n = 46,350) and 871 plasma metabolite (n = 8299) datasets. We used druggability analysis to prioritize metabolites with therapeutic potential. Results: Our MR analysis identified 32 plasma metabolites whose levels were protective against the risk of ASD, including 5 alpha-androstan-3 alpha, 17 beta-diol disulfate (odds ratio (OR): 0.94, 95% CI: 0.90-0.97) and 11beta-hydroxyetiocholanolone glucuronide (OR: 0.95, 95% CI: 0.92-0.98). Additionally, 12 metabolites were found to be positively associated with the risk of ASD, including indoleacetylglutamine (OR: 1.04, 95% CI: 1.01-1.08) and sphingomyelin (d18:1/24:1, d18:2/24:0) (OR: 1.06, 95% CI: 1.01-1.11). Some metabolites may be regulated through drug intervention, including sphingomyelin, chiro-inositol, carotene diol (1)/(2), and glycerol. Genetic variation contributing to ASD may increase the abundance of five metabolites, including deoxycholic acid glucuronide (OR: 1.18, 95% CI: 1.03-1.34); meanwhile, the abundance of 27 metabolites, including stearoyl choline (OR: 0.80, 95% CI: 0.69-0.92) may be causally reduced. Conclusions: Our MR analysis uncovered bidirectional causal associations between certain plasma metabolites and ASD, suggesting that these metabolites could be biomarkers for ASD and paving the way for novel therapeutic targets in ASD phenotypes.