Systematic multi-omic deconvolution of the clinical heterogeneity of Down syndrome

Persons with Down syndrome, the genetic condition caused by trisomy 21, are at high risk of developing various co-occurring conditions affecting all major organ systems. Recent multi-omic studies have revealed the profound impacts of trisomy 21 on human biology, including strong effects on the transcriptome, proteome, metabolome, and immunome. However, it is unclear whether these changes are conserved effects of trisomy 21 versus effects associated with specific co-occurring conditions. Here we report a multi-omic investigation of 100 clinical phenotypes in a cohort of 356 individuals with Down syndrome, which identifies many phenotype-associated signatures of potential clinical significance. Obesity associates with the largest number of changes in the proteome and metabolome of persons with Down syndrome, with dysregulation of key hormonal, growth signaling, and neurotransmitter systems. Congenital heart defects associate with the strongest changes in the whole blood transcriptome, concurrent with interferon hyperactivity and immune remodeling. Key signatures dysregulated by trisomy 21 are exacerbated in those with seizure disorders, gastrointestinal conditions, and various cardiopulmonary diseases. These analyses implicate immune dysregulation as a driver of diverse clinical phenotypes in Down syndrome beyond canonical autoimmune disorders. Altogether, these results support the development of personalized medicine approaches for the clinical management of Down syndrome.