Wanying Zhu, Hung-Hsin Chen, Heather M Highland, Corey Giles, Peter J Meikle, Phillip Lin, Lauren E Petty, Hannah G Polikowsky, Alex S Petty, Mohammad Y Anwar, Xinruo Zhang, Joanne E Curran, Elizabeth G Frankel, Rashedeh Roshani, Joshua M Landman, Gabriela S Castrodad-Rivera, Caroline Herndon, Joseph B McCormick, Susan P Fisher-Hoch, Penny Gordon-Larsen, Eric R Gamazon, Kari E North, Jennifer E Below
While lipids have been extensively investigated, genetic regulation of the circulating lipidome in diverse populations remains poorly understood. We conducted a lipidome-wide GWAS of 830 lipid species in 2,287 Hispanic/Latino participants and performed predictive modeling across omics layers. We identified 7,593 genome-wide significant SNPs mapping to 208 genes. Conditional analysis disentangled the long-range linkage disequilibrium artifacts from the pleiotropic FADS1/2/3 cluster. Separately, we discovered an association at the GPLD1 locus for a circulating ceramide. Colocalization revealed shared genetic architecture with conventional lipids alongside distinct, species-specific pathways. Incorporating Native/Indigenous American eQTLs within a multi-omic framework uncovered 62 likely regulatory genes missed by European-centric gene expression models. Finally, genetically regulated predictive models demonstrated performance declining from transcriptomics to proteomics to lipidomics, reflecting increased distance from gene action along the molecular cascade. Our study provides a genetic landscape of lipid metabolism in a highly burdened population and highlights the challenges in predicting lipid abundance.