Multiomics of Human Obesity and Related Multisystem Diseases

Context Efforts to characterize the shared molecular risk factors that contribute to obesity and the downstream disease sequelae it triggers have been limited. Objective We aimed to identify functional genes with evidence for both causal and consequential effects on obesity-related traits and their downstream sequalae using integrated genomic and proteomic data. Methods We investigated the association of obesity-related traits with 2912 plasma proteins in 259 individuals from the Cameron County Hispanic Cohort with validation of results in ∼45 000 participants from the UK Biobank. Through colocalization and Mendelian randomization, we assessed evidence for the shared underpinning and the causal direction of significant proteins with respect to obesity and obesityassociated illnesses. We used gene ontology and cell- and tissue-specific protein and transcriptional activity patterns of the genes encoding target proteins to illuminate the functional relevance of implicated pathways. We additionally investigated the suitability of target proteins as potential therapeutic targets for drug development. Results Of the 122 significantly associated proteins with obesity metrics at a false discovery adjusted level (false discovery rate < 0.05), 121 replicated in UKBB. Most function in adipogenesis, inflammation, glucose metabolism, and neural and appetite regulation. Eighty of 121 replicated proteins showed evidence of statistical causality for obesity or obesity-associated illnesses. Those causally linked showed elevated transcript abundance in adipose and brain tissues and adipocytes. The promising weight reduction potential of several target proteins highlights their suitability for future pharmaceutical repurposing. Conclusion Our analyses revealed key regulatory mechanisms influenced by and influencing obesity, offering valuable targets for biomarkers and clinical interventions.