Genetic drivers of protein changes over time: Findings, considerations, and approaches in TOPMed cohorts and UK Biobank
Year: 2026
Type: preprint
Abstract: Age is a major risk factor for many diseases, but the biological processes driving aging are heterogeneous across individuals. Efforts to untangle differences between chronological and biological age have focused on identifying age-associated markers, such as 'omics clocks. Many 'omics features, including proteins, are strongly associated with age, and genetics contribute to variance in these measures. However, few studies have identified genetic drivers of interindividual variability in 'omics changes over time. Using longitudinal proteomics data (Olink 3k) from the Multi-Ethnic Study of Atherosclerosis (MESA), we calculated a protein slope for each individual (n=2,007) and protein (n=2,737) across 3 visits spanning 14-18 years, then conducted a genome-wide analysis for each slope, both with and without adjusting for baseline protein level. Subsets in UK Biobank (UKB; n=948) and CARDIA (n=1,328) with longitudinal proteomics data were used for replication. We considered additional methods for modeling of protein change and variability, including linear mixed models, SNP-by-age interactions, and variance quantitative trait loci. Without baseline adjustment, only 19 proteins (20 credible sets) had a slope pQTL in MESA, with poor replication in UKB and CARDIA. With baseline adjustment, 607 proteins (698 credivle sets) had a slope pQTL and over 70% replicated in CARDIA and/or UKB; such baseline adjusted models may, however, be subject to collider bias. Longitudinal and cross-sectional interaction models identified fewer than 14 pQTLs, suggesting they were generally underpowered; but 73% of proteins with a variance pQTL also had a slope pQTL. By examining effect direction concordance, replication rate, directed acyclic graphs, and signal overlap with other models we demonstrate that many baseline-adjusted slope pQTLs may be arising due to model misspecification or regression to the mean. Overall, our results highlight considerations for modeling strategies of change phenotypes and build on understanding of potential genetic mechanisms influencing interindividual proteome changes over time.
Authors: Madeline G. Gillman, Han Chen, Annie Green Howard, Michael Mi, Zsu-Zsu Chen, Clary B. Clish, Daniel E. Cruz, Peter Durda, Craig Johnson, Ani W. Manichaikul, Suna Onengut, Prashant Rao, Usman A. Tahir, Kent D. Taylor, Russell P. Tracy, Alexis C. Wood, Robert E. Gerszten, Lifang Hou, Ravi Shah, Jerome I. Rotter, Stephen S. Rich, Laura M. Raffield
Institutions: University of North Carolina at Chapel Hill, New York University, Beth Israel Deaconess Medical Center, Harvard University, Broad Institute, University of Vermont, University of Washington, University of Virginia, The Lundquist Institute, Harbor–UCLA Medical Center, Baylor College of Medicine, Northwestern University, Vanderbilt University Medical Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: MESA, Wake Forest Clinical and Translational Science Award, Large Scale Sequencing and Analysis of Genomes, Rare variants and NHLBI traits in deeply phenotyped cohorts, MESA, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, MESA, Rare variants and NHLBI traits in deeply phenotyped cohorts, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, CHARGE consortium: omics discovery for CVD and aging phenotypes, Institute for Clinical and Translational Research, MESA, MESA, Clinical and Translational Science Award, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, UCLA Clinical and Translational Science Institute
OpenAlex ID: W7201848786