1086-OR: An eQTL Resource of Insulin Target Tissues from Latin American Participants Reveals Ancestry-Specific Regulatory Mechanisms of Type 2 Diabetes and Lipid Traits

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Introduction and Objective: Type 2 diabetes (T2D) disproportionately impacts Latin Americans. Genome wide association studies (GWAS) in Latin Americans identify T2D and lipid trait associated variants, but existing expression quantitative trait loci (eQTL) resources are primarily comprised of European ancestry and limit interpretation of non-coding variants enriched in Latin Americans. We present the Latin American Genotype-Tissue Expression (LAGTEx) resource, with 913 samples from 360 individuals across four insulin-responsive tissues—subcutaneous and visceral adipose (SAT, VAT), liver, and muscle. Our current dataset contains 52 liver, 145 SAT, 102 VAT, and 68 muscle samples. Methods: Bulk RNA-seq was done using Ilumina Novaseq X. Genotypes were imputed with TOPMed. RNA-seq counts were normalized by DESeq2. eQTL mapping used FastQTL, adjusting for age, sex, BMI, batch, and genetic and expression confounders. Finemapping used SuSiE. Coloc R was used for colocalization with GWAS. Results: We identified 166, 2328, 700, and 219 independent cis-eQTLs in liver, SAT, VAT, and muscle, associated with 161, 1685, 616, and 215 genes. 211 signals colocalized (PP.H4 > 0.7) with T2DGGI T2D GWAS loci. 46 were previously reported; the rest were novel, including 37 effector genes identified for the first time. SKP2 (rs10461962) colocalized in liver (PP.H4 = 0.73); the variant is enriched in Latin Americans (MAF = 0.035) rare in Europeans (MAF = 0.0002), and absent from GTEx. 14 signals colocalized with Hispanic lipid GWAS, including ANGPTL8 (rs3760782) in SAT, (PP.H4 = 0.90) which regulates lipid metabolism via lipoprotein lipase inhibition; the HDL-decreasing allele decreases ANGPTL8 expression, is enriched in Latin Americans and absent from GTEx. Conclusion: LAGTEx enables assessment of regulatory effects from variants enriched in Latin American populations in insulin-responsive tissues, addressing a key limitation of resources and improving understanding of ancestry-specific metabolic traits. Disclosure H. Wadhwa: None. L. Szczerbinski: Research Support; Current; Novo Nordisk. Consultant; Current; Eli Lilly and Company. F. Barajas-Olmos: None. K. Taylor: None. H. García-Ortiz: None. C. Contreras-Cubas: None. A. Martínez-Hernádez: None. V. Kaur: None. A. Huerta: None. A. Janucik: None. A. Kretowski: None. M. Claussnitzer: Consultant; Current; Novo Nordisk, Pfizer Inc. Advisory Panel; Ended; SixPeaks Bio. Advisory Panel; Current; Nestlé. Stock/Shareholder; Current; Sidera Bio, Waypoint Bio. I. Cebola: None. L. Orozco: None. J. Mercader: None. Funding NHGRI (U01HG011723), R01DK137993 and U01 DK140757, AMP CMD RFP 6 FNIH, Medical University of Bialystok (MUB) grant from the Ministry of Science and Higher Education (Poland), Novo Nordisk Foundation (NNF21SA0072102).

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