Fig. 2

Characterization of metabolite intensity differences identified in the prefrontal cortex of ASD individuals. a Summary of top functional pathways enriched in genes linked to metabolites represented in different categories using KEGG annotation. The categories include: all 202 ASD-related metabolites identified using ANCOVA (All); ASD-related metabolites within each module (modules 1–4); and ASD metabolic predictors identified using logistic regression (log-regression). The size of each circle is proportional to the number of genes within the pathway linked to metabolites in a given category (smaller circles correspond to a smaller number of genes). The color of each circle indicates the BH-corrected enrichment p-values. b Simplified schematic representation of the glutathione pathway based on the KEGG annotation. Circles represent metabolites. Circle colors indicate the direction and significance of the difference. The double coloring of L-γ-glutamyl-L-amino acid and L-amino acid represent intensity changes of different compounds that fall under this putative annotation. Stars mark genes containing genetic variants associated with the ASD according to SFARI and GRASP databases^49,50. c The intensities of five metabolites from the glutathione metabolism pathway showing differences in ASD: glutathione, L-γ-glutamylcysteine, L-cysteinylglycine, glutathione disulfide, and 5-oxoproline. Boxes show the first and the third quartiles and the median of the data; the whiskers extend to the minimum and maximum data values located within 1.5 interquartile range from the box. Dots indicate actual intensity values for individual samples. Colors represent ASD individuals (gray) and control individuals (red). Stars indicate the significance of differences between metabolite intensity in ASD individuals and controls (ANCOVA, BH-corrected p-value: ** < 0.01; ns > 0.01). d Average area under the receiver operating characteristic curve (ROC AUC) calculated using logistic regression with optimal parameters performed 500 times on different subsets of the individuals. e Distributions of the proportions of genes showing expression difference in ASD (|log2 fold change|>0.2) among genes linked to each of 202 ASD-related metabolites (gray curve) and the other metabolites detected in our study (red curve). Expression data was taken from ref. ⁴⁰. Panels show the distribution in three brain regions: left—frontal cortex, center—temporal cortex, right—cerebellum