Genetically regulated gene expression and proteins revealed discordant effects

Although gene-expression (GE) and protein levels are typically strongly genetically regulated, their correlation is known to be low. Here we investigate this phenomenon by focusing on the genetic background of this correlation in order to understand the similarities and differences in the genetic re...

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Bibliographic Details
Published in:PloS one Vol. 17; no. 5; p. e0268815
Main Authors: Pott, Janne, Garcia, Tarcyane, Hauck, Stefanie M., Petrera, Agnese, Wirkner, Kerstin, Loeffler, Markus, Kirsten, Holger, Peters, Annette, Scholz, Markus
Format: Journal Article
Language:English
Published: United States Public Library of Science 23.05.2022
Public Library of Science (PLoS)
Subjects:
Analysis
Biology and Life Sciences
Biomarkers
Cardiovascular disease
Coronary heart disease
Correlation
CXCL16 protein
Gene expression
Gene loci
Genes
Genetic aspects
Genomes
Genotype & phenotype
Health aspects
Interleukin 6
Interleukin 6 receptors
Medicine and Health Sciences
Protein expression
Proteins
Proteomics
Risk factors
Tissues
Germany
ISSN:1932-6203, 1932-6203
Online Access:Get full text
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Summary:Although gene-expression (GE) and protein levels are typically strongly genetically regulated, their correlation is known to be low. Here we investigate this phenomenon by focusing on the genetic background of this correlation in order to understand the similarities and differences in the genetic regulation of these omics layers. We performed locus-wide association studies of 92 protein levels measured in whole blood for 2,014 samples of European ancestry and found that 66 are genetically regulated. Three female- and one male-specific effects were detected. We estimated the genetically regulated GE for all significant genes in 49 GTEx v8 tissues. A total of 7 proteins showed negative correlations with their respective GE across multiple tissues. Finally, we tested for causal links of GE on protein expression via Mendelian Randomization, and confirmed a negative causal effect of GE on protein level for five of these genes in a total of 63 gene-tissue pairs: BLMH, CASP3, CXCL16, IL6R, and SFTPD. For IL6R, we replicated the negative causal effect on coronary-artery disease (CAD), while its GE was positively linked to CAD. While total GE and protein levels are only weakly correlated, we found high correlations between their genetically regulated components across multiple tissues. Of note, strong negative causal effects of tissue-specific GE on five protein levels were detected. Causal network analyses revealed that GE effects on CAD risks was in general mediated by protein levels.
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Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0268815