Year: 2026
Type: preprint
Abstract: Background Protein EpiScores are DNA methylation (DNAm)-derived predictors of circulating protein levels that may provide accessible biomarkers of disease-related molecular variation. However, because these models were developed in blood, it remains unclear whether they preserve interindividual variation when applied to other tissues. We evaluated the cross-tissue concordance of blood-trained protein EpiScores in matched donors from the Genotype-Tissue Expression (GTEx) project. Methods We applied 109 published protein EpiScores to DNAm from whole blood and six matched non-blood tissues in 54 donors contributing 158 blood–tissue pairs. Fifteen scores had unusable variation, leaving 94 estimable scores per tissue and 564 comparisons. Positive concordance required Pearson r and Spearman ρ ≥0.50; strong concordance required both ≥0.70. Benjamini–Hochberg false-discovery-rate (FDR) correction was applied separately across all comparisons for each method. Leave-one-out analyses assessed donor influence, and partial Pearson correlations evaluated sensitivity to available covariates. Protein annotations, composites, and donor strata were examined descriptively. Results Ninety-seven of 564 comparisons (17.2%) met the positive-concordance criterion, and 73 of these (75.3%) met the leave-one-out stability criteria. Lung showed the broadest correspondence: median absolute Pearson r was 0.594, 56/94 scores were concordant, and 49 were stable. After covariate adjustment, median absolute partial r in lung was 0.522 and 68/94 scores had global q <0.05. Among initially concordant pairs, 48/56 in lung retained partial r ≥0.50 and q <0.05, compared with 3/10 in colon, 1/2 in kidney cortex, and 0/3 in prostate. Breast and ovary were too small for adjusted analyses. Exploratory donor-cohort differences did not survive FDR correction. Conclusions Blood-trained protein EpiScores showed broad correspondence in lung that persisted after adjustment for available covariates. Initially concordant findings in the other tissues eligible for adjustment were mostly covariate-sensitive. These results prioritize score–tissue combinations for replication and molecular validation; they do not establish that blood EpiScores measure local tissue protein abundance.
Institution: Case Western Reserve University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223575567