ABSTRACT: How humans differ from one another at the molecular level and the impact of ethnicity, age and environmental factors such as diet and geography are poorly understood. To address this gap, we analyzed 322 nominally healthy individuals from diverse ethnic backgrounds located in distinct geographical regions, using (1) deep multi-omic profiling - including genome sequencing, transcriptomics, glycomics, targeted and untargeted metabolomics, lipidomics, proteomics, 16S microbiota sequencing, metaproteomics, metallomics, and metabolic hormone and pathogen profiling, (2) clinical data collection, and (3) comprehensive lifestyle surveys. Our integrative analysis revealed several key findings: associations between molecular profiles (transcripts, proteins, metabolites, lipids, glycans, and microbiota) and age, ethnicity, and geographical residence (including diet) among healthy individuals; ethnicity-specific genetic polymorphisms in key genes governing whole-body homeostasis, particularly in lipid/carbohydrate metabolism and neuroinflammation pathways; and variation in the abundance of key proteins such as the TERF2 interacting protein (TERF2IP) which is critical for cellular aging, genome stability, and protection against chromosomal degradation. These findings hold significant translational value, particularly in understanding ethnicity as a risk factor for autoimmune diseases. Many ethnicity-associated molecules identified in our study interact with existing therapeutic drugs, highlighting the potential need for ethnicity-specific drug dosing adjustments. Furthermore, our results suggest that geographical factors influence ethnic patterns, which may, in turn, affect longevity. individuals with European ancestry exhibited a lower phenotypic age, while those of Asian ancestry showed a higher phenotypic age when living outside their ancestral regions. By providing both a comprehensive baseline dataset of multi-omic variation in healthy individuals and critical insights into the molecular basis of human diversity, our study enhances our understanding of how environmental and genetic factors influence phenotypic and molecular traits and potentially augments individualized health approaches.
Ulrike Kusebauch 
