Transcriptomic signatures of lipids in blood provide hypotheses of functional mechanisms linked to lipid metabolism and immune-cell regulation.
11 affiliations
- 1Division of Public Health Sciences, Fred Hutchinson Cancer Center, 1100 Fairview Avenue N, Seattle, WA 98109, United States.
- 2Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 170 Rosenau Hall, CB #7400, 135 Dauer Drive, Chapel Hill, NC 27599, United States.
- 3Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, 72 E. Concord St Robinson (B), Boston, MA 02118, United States.
- 4Framingham Heart Study, 73 Mt. Wayte Ave, Ste 2, Framingham, Massachusetts, Boston, MA 01702, United States.
- 5Population Sciences Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD 20892, United States.
- 6Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Ave, 507 Light Hall, Nashville, TN 37232, United States.
- 7Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 2215 Garland Ave, 507 Light Hall, Nashville, TN 37232, United States.
- 8Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave, Boston, MA 02118, United States.
- 9The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, New York, NY 10029, United States.
- 10Department of Epidemiology, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL 35233, United States.
- 11Department of Epidemiology, School of Public Health, University of Washington, Box #351619, Seattle, WA 98195, United States.
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.
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BibTeX
@article{lundin2026transcriptomic,
title = {{Transcriptomic signatures of lipids in blood provide hypotheses of functional mechanisms linked to lipid metabolism and immune-cell regulation.}},
author = {Jessica I Lundin and Mariaelisa Graff and Jeff Haessler and Xinruo Zhang and Yanwei Cai and Harriett Fuller and Nancy Heard-Costa and Tianxiao Huan and Roby Joehanes and Joshua M Landman and Gina Marie Peloso and Yuxuan Wang and Zhe Wang and Jennifer E Below and Daniel Levy and Kari E North and Alex P Reiner and Ryan Zukowski and Ulrike Peters and Charles Kooperberg},
journal = {Human molecular genetics},
year = {2026},
month = oct,
doi = {10.1093/hmg/ddag113},
url = {https://europepmc.org/article/MED/42955849},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Transcriptomic signatures of lipids in blood provide hypotheses of functional mechanisms linked to lipid metabolism and immune-cell regulation.
AU - Jessica I Lundin
AU - Mariaelisa Graff
AU - Jeff Haessler
AU - Xinruo Zhang
AU - Yanwei Cai
AU - Harriett Fuller
AU - Nancy Heard-Costa
AU - Tianxiao Huan
AU - Roby Joehanes
AU - Joshua M Landman
AU - Gina Marie Peloso
AU - Yuxuan Wang
AU - Zhe Wang
AU - Jennifer E Below
AU - Daniel Levy
AU - Kari E North
AU - Alex P Reiner
AU - Ryan Zukowski
AU - Ulrike Peters
AU - Charles Kooperberg
PY - 2026
DA - 2026/10/01
JO - Human molecular genetics
DO - 10.1093/hmg/ddag113
UR - https://europepmc.org/article/MED/42955849
AB - 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.
SN - 0964-6906
SN - 1460-2083
ER -