Genetic Architecture of the Human Blood Lipidome: Integrative Multi-Omics Analyses and Predictive Modeling in a Hispanic/Latino Cohort

Abstract

While conventional lipids such as HDL, LDL, and triglycerides are routinely measured in clinical settings, the broader human blood lipidome provides a more detailed view of metabolic pathways underlying disease. However, its genetic regulation remains less explored, particularly in underrepresented populations. We performed genome-wide association studies (GWAS) of 830 lipid species from 48 classes in 2,287 Hispanic/Latino participants of the Cameron County Hispanic Cohort, followed by fine-mapping, colocalization, and predictive modeling analyses. We identified 7,593 significant variants across 639 loci, including 277 novel SNPs and 10 novel genes such as ALDH5A1, GPLD1, and PLAAT2. Colocalization revealed extensive shared genetic signals between lipid species and conventional lipids. Finally, genetically regulated models showed decreasing predictive performance across omic layers, reflecting the increasing distance from gene action. Together, these results illuminate the genetic architecture of the circulating lipidome in a Hispanic/Latino population and provide insights into shared and ancestry-specific mechanisms influencing lipid metabolism and cardiometabolic disease risk.