Dissecting Genetic and Environmental Determinants of Plasma Molecular Signatures and Their Link to Type 2 Diabetes Risk

作者：Magdalena Sevilla-González, N. Wang, Paul A. Hanson, Allison Bebo, Daniel S. Hitchcock, Sarah Hsu, Kenneth E. Westerman, Sara J. Cromer, Valene Garr Barry, Yonah Borns-Weil, Yixin Zhang, Ori Ben-Yossef, Chirag J. Patel, Nora Franceschini, Kent D. Taylor, Julián Ávila-Pacheco, Clary B. Clish, Robert E. Gerszten, Laura M. Raffield, Charles Kooperberg, Stephen S. Rich, Josée Dupuis, Jerome I. Rotter, Ching‐Ti Liu, James B. Meigs, Alisa K. Manning · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.11.26.25341007 · 被引用次数：1 · 研究领域：Genetic Associations and Epidemiology、Nutrition, Genetics, and Disease、Diabetes, Cardiovascular Risks, and Lipoproteins

Background: Type 2 diabetes (T2D) is a heterogeneous disease shaped by both genetic, environmental, cultural, and socioeconomic factors, with well-documented disparities in incidence across populations. The molecular pathways underlying these disparities, however, remain poorly understood. Plasma metabolites and proteins integrate both genetic and environmental influences on type 2 diabetes (T2D) risk, providing insight into disease mechanisms. We aimed to quantify the variance in these molecular profiles explained by environmental and genetic ancestry domains and to apply causal inference approaches to identify environmentally and genetic ancestry influenced pathways contributing to T2D risk. Methods: We analyzed plasma proteomic and metabolomic profiles from 3,360 MESA participants (51.6% female), and in 1,333 participants from the Women's Health Initiative. To characterize the sources of variance in plasma proteomic and metabolomic profiles, we performed variance decomposition partitioning into four domains: biological (age, sex, BMI), genetic ancestry (principal components), lifestyle (smoking, alcohol intake, diet), and social determinants (self-reported race and ethnicity, income, education). To assess causal pathways towards T2D risk, we applied two-sample Mendelian Randomization to disentangle environmental and genetic contributors to T2D risk. Results: The largest share of variance in proteomic and metabolomic profiles was explained by biological and lifestyle factor...