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BackgroundThe molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.MethodsIn this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches).ResultsWe identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn's disease.ConclusionsOur data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.

Original publication

DOI

10.1186/s13073-020-00754-1

Type

Journal article

Journal

Genome medicine

Publication Date

07/2020

Volume

12

Addresses

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Keywords

Humans, Disease Susceptibility, Inflammation, Proteins, Blood Proteins, Inflammation Mediators, Computational Biology, Genomics, Age Factors, DNA Methylation, Gene Expression Regulation, Epigenesis, Genetic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Epigenomics, Healthy Volunteers, Biomarkers