An integrated multi-omic natural history study of human development, sexual dimorphism, and the effects of trisomy 21

Human development involves multiple signaling pathways acting concertedly in an age- and sex-specific fashion. Trisomy 21, the genetic cause of Down syndrome, dysregulates human development leading to both early neurodevelopmental delays and atypical accelerated aging through unknown mechanisms. Here, we report an integrated multi-omic analysis of the effects of age, sexual dimorphism, and trisomy 21 in hundreds of research participants using matched transcriptome, proteome, metabolome, and immunome datasets. We find that age-related changes peak during puberty and decrease steadily afterwards, with minor changes past early adulthood. The effects of sexual dimorphism are negligible in early childhood but rise sharply during gonad activation and remain strong during reproductive age. Trisomy 21 impacts all life stages, with clear age-specific effects, whereby individuals with Down syndrome display varying pathophysiology at different life stages. Altogether, these analyses provide an advanced understanding of how human development is affected by sex chromosomes and a viable aneuploidy. Using multi-omic analyses, the authors reveal how aging, sex, and trisomy 21 shape human biology across the lifespan, showing that age- and sex-specific changes peak during puberty and adulthood, while trisomy 21 exerts differential effects over time.