Faculty, Staff and Student Publications
Publication Date
10-11-2022
Journal
Nature Communications
Abstract
Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
Keywords
Alleles, Cholesterol, LDL, Genome-Wide Association Study, Humans, Lipids, Whole Genome Sequencing
DOI
10.1038/s41467-022-33510-7
PMID
36220816
PMCID
PMC9553944
PubMedCentral® Posted Date
10-11-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes