{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T10:31:49Z","timestamp":1786357909771,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,7]]},"group-title":"Genetics","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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 \u2019omics clocks. Many \u2019omics 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 \u2019omics changes over time.<\/jats:p>\n                <jats:p>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\u201318 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.<\/jats:p>\n                <jats:p>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.<\/jats:p>\n                <jats:p>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.<\/jats:p>","DOI":"10.64898\/2026.08.03.742409","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:45:21Z","timestamp":1786103121000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic drivers of protein changes over time: Findings, considerations, and approaches in TOPMed cohorts and UK Biobank"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6091-3238","authenticated-orcid":false,"given":"Madeline G.","family":"Gillman","sequence":"first","affiliation":[{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-4923","authenticated-orcid":false,"given":"Han","family":"Chen","sequence":"additional","affiliation":[{"name":"Rory Meyers College of Nursing, New York University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie Green","family":"Howard","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9441-675X","authenticated-orcid":false,"given":"Zsu-Zsu","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8259-9245","authenticated-orcid":false,"given":"Clary B.","family":"Clish","sequence":"additional","affiliation":[{"name":"Broad Institute of Harvard and MIT, Cambridge, MA, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Cruz","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Durda","sequence":"additional","affiliation":[{"name":"Department of Pathology Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Washington, Seattle, WA, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ani W.","family":"Manichaikul","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Virginia, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6563-8334","authenticated-orcid":false,"given":"Suna","family":"Onengut","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Virginia, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-4677","authenticated-orcid":false,"given":"Prashant","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Usman A.","family":"Tahir","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent D.","family":"Taylor","sequence":"additional","affiliation":[{"name":"The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center, Torrance, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell P.","family":"Tracy","sequence":"additional","affiliation":[{"name":"Department of Pathology Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-2119","authenticated-orcid":false,"given":"Alexis C.","family":"Wood","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Gerszten","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifang","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, 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