Faculty, Staff and Student Publications
Publication Date
8-6-2024
Journal
Human Molecular Genetics
Abstract
Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.
Keywords
Humans, Precision Medicine, Biomarkers, Inflammation, Genome-Wide Association Study, Whole Genome Sequencing, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genetic Predisposition to Disease, Female, Interleukin-6, inflammation biomarkers, whole genome sequencing data, rare variant aggregate test, genome-wide association studies, Trans-Omics for Precision Medicine (TOPMed) consortium
DOI
10.1093/hmg/ddae050
PMID
38747556
PMCID
PMC11305684
PubMedCentral® Posted Date
5-15-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes