Hum Mol Genet. 2026 Oct 28;35(22):ddag113. doi: 10.1093/hmg/ddag113.
ABSTRACT
Blood lipids are well-established risk factors for cardiovascular and other chronic diseases, yet the underlying functional mechanisms remain unclear. We conducted a large-scale, genome-wide transcriptome analysis of serum lipid levels using whole blood RNA-sequencing data from 6898 individuals of diverse races and ethnicities (17% Black or African American, 15% Hispanic Latino/a, 68% White). We utilized mixed-effects linear regression and meta-analyzed four discovery datasets (n = 4398 participants), identifying significant associations for 27 genes with low-density lipoproteins (LDL), 974 with high-density lipoproteins (HDL), 1229 with triglycerides (TRIG), and 276 with total cholesterol (TCHO). Two replication datasets (n = 2500 participants) confirmed 3, 55, 380, and 31 genes, respectively. Enrichment analysis revealed lipid metabolic processes for LDL, HDL, and TCHO associated genes, including LDLR, NPC2, and SQLE for LDL and TCHO, while TRIG associated genes highlighted immune and allergic response, cancer, and molecular signaling gene enrichment pathways. To infer causality, we performed bidirectional two-sample Mendelian randomization (MR) and colocalization analyses. MR identified the expression of 8 genes as possibly causal for lipid levels; notable EEPD1 expression, linked with cellular cholesterol homeostasis, was inversely linked with TRIG levels. We also identified novel variants shared with LDL levels and gene expression of DDAH2, associated with cardiovascular disease, and TRIG level and expression of FCGRT, linked with maintaining triglyceride homeostasis. Phenome-wide enrichment analyses reported TRIG associated genes were enriched in secondary malignancy of bone suggesting broader systemic health implications of modified lipid levels. These findings highlight novel associations and genetic regulatory mechanisms as potential therapeutic targets for lipid dysregulation.
PMID:42955849 | DOI:10.1093/hmg/ddag113