Genome-Wide Association Study Identifies Novel and Confirms Established Loci Associated with Serum Lipids Levels in Brazilians

Abstract Dyslipidemia is an important risk factor for cardiovascular diseases and can result from genetic and environmental influences. Most genome-wide association studies (GWAS) have been conducted in European populations, limiting our understanding of polymorphisms involved in lipid levels in admixed populations such as Brazilians. Therefore, this study aimed to identify genetic variants associated with lipid traits and develop polygenic risk scores (PRS) for dyslipidemia prediction in a large cohort of Brazilians. We performed GWAS of lipid phenotypes using 19,016 Brazilian individuals previously genotyped with SNP array and with available biochemical lipid measurements. After quality control and imputation, GWAS analyses were conducted separately for triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL cholesterol (non-HDL-C). Trans-ancestry PRS were constructed using PRS-CSx. A set of 161 genome-wide significant SNPs were identified across lipid traits, including 52 previously reported in different populations, and many others representing potential novel associations for all phenotypes except LDL-C. PRS models showed consistent associations with lipid levels, with increasing prevalence of elevated TC, LDL-C, non-HDL-C, and TG across higher PRS deciles. The area under the curve (AUC) values ranged from 0.62 to 0.66 across traits, with the highest performances for TC, non-HDL-C and TG. This study provides new insights into the genetic architecture of lipid traits in an admixed Brazilian population. Our findings underscore the relevance of conducting GWAS in diverse populations, support the use of PRS for risk stratification and prevention, and point to novel targets for drug development.