Figshare · Apr 8, 2026
From GWAS Loci to Biological Pathways: A TWAS of Blood Lipids Identifies Novel Mechanisms and Precision-Medicine Opportunities
By Cheung N
Dyslipidemia is a major modifiable risk factor for cardiovascular disease, yet many loci identified by genome-wide association studies remain difficult to connect to specific genes, tissues, and biological mechanisms. In this study, a transcriptome-wide association study was carried out using European-ancestry summary statistics from the 2021 Global Lipids Genetics Consortium meta-analysis, which included about 1.32 million individuals, together with GTEx v8 expression models across six metabolically relevant tissues. Gene-set enrichment analyses showed several coherent biological programs linked to HDL-C, LDL-C, logTG, non-HDL-C, and total cholesterol. The strongest meta-across-tissues signal was the REACTOME telomere maintenance pathway, which showed opposite directions for HDL-C and logTG, and FEN1 was the main driver gene. The HALLMARK apoptosis pathway was negatively associated with HDL-C but positively associated with LDL-C and non-HDL-C, with IGF2R as the leading contributor. NAD-related pathways, including biosynthesis and transport, and the CAMKK-AMPK signaling cascade also showed opposing directions for LDL-C and total cholesterol. An adult oligodendrocyte gene set was strongly positively associated with logTG and was driven in part by ABCA8. The HLA complex showed marked allelic heterogeneity, with HLA-DQB1 and HLA-DQB2 displaying mirror-image effects across traits. Together, these findings suggest that genetically predicted differences in telomere integrity, apoptosis, NAD-AMPK metabolic balance, glial lipid handling, and immune activation converge on hepatic lipoprotein metabolism and systemic lipid levels. Although the analysis was based on European-ancestry data, it builds directly on the multi-ancestry framework of the original GWAS and points to pathways that may contribute to residual cardiovascular risk. Pathway-informed polygenic scores and targeted modulation of these programs, including NAD precursors and senescence-modifying agents, may support more precise lipid management and could help reduce health disparities if extended to diverse populations. Functional validation and prospective studies will be needed before these associations can be translated into clinical use.