Abstract
Down syndrome (DS), caused by trisomy 21 (T21), results in immune and metabolic dysregulation. People with DS experience co-occurring conditions at higher rates than the euploid population. However, the interplay between immune and metabolic alterations and the clinical manifestations of DS are poorly understood. Here, we report an integrated analysis of immunometabolic pathways in DS. Using multi-omics data, we infered cytokine-metabolite relationships mediated by specific transcriptional programs. We observed increased mediation of immunometabolic interactions in those with DS compared to euploid controls by genes in interferon response, heme metabolism, and oxidative phosphorylation. Unsupervised clustering of immunometabolic relationships in people with DS revealed subgroups with different frequencies of co-occurring conditions. Across the subgroups, we observed distinct mediation by DNA repair, Hedgehog signaling, and angiogenesis. The molecular stratification associates with the clinical heterogeneity observed in DS, suggesting that integrating multiple omic profiles reveals axes of coordinated dysregulation specific to DS co-occurring conditions.