{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T02:39:12Z","timestamp":1772764752058,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,3]]},"group-title":"Genetic and Genomic Medicine","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the present study, we conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c in up to 489,309 individuals without diabetes from seven different population groups. In total, 16 loci were identified to interact with sleep duration \u2014 six with short sleep and ten with long sleep. Of these, four loci were identified through cross-population meta-analysis. Mapped genes exhibit pathway connections to pericyte apoptosis, NMDA receptor activity, the GLUT1 receptor, neurological health, and sleep architecture. Eleven loci (\n                  <jats:italic>VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, MAPT<\/jats:italic>\n                  ) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identify divergent biological mechanisms for short and long sleep duration influencing glycemic control, suggesting specific pathways of intervention for precision medicine approaches to diabetes prevention and management.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>The biological mechanisms of how sleep duration impacts type 2 diabetes pathogenesis and glycemic control are unclear.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>This study reveals 16 loci (11 novel) that interact with either short or long sleep duration to influence hemoglobin A1c, fasting glucose, or fasting insulin. Short and long sleep duration loci were non-overlapping.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Regulation of copper and diacylglycerol levels appear as distinct cellular mechanisms implicated by long and short sleep duration loci respectively.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Identified gene targets present insight for potential type 2 diabetes therapeutic design approaches related to JIP1-JNK interaction disruption, pericyte health, NMDA receptor activity, anti-inflammatory and leptin-enhancing dietary supplements, and serpins.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.02.26346498","type":"posted-content","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:15:14Z","timestamp":1772583314000},"source":"Crossref","is-referenced-by-count":0,"title":["Gene-by-Sleep Duration Interaction for Glycemic Traits in over 480,000 Individuals"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1486-7495","authenticated-orcid":false,"given":"Heming","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0036-9970","authenticated-orcid":false,"given":"Pavithra","family":"Nagarajan","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clint L","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"name":"Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy R","family":"Bentley","sequence":"additional","affiliation":[{"name":"Center for Research on Genomics and Global Health, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond","family":"Noordam","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands"},{"name":"Health Campus the Hague\/Public Health and Primary Care, Leiden University Medical Center, the Hague, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-1868","authenticated-orcid":false,"given":"Kenneth E","family":"Westerman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Harvard Medical School, Boston, MA, USA"},{"name":"Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aldi T","family":"Kraja","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey R","family":"O\u2019Connell","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Schwander","sequence":"additional","affiliation":[{"name":"Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changwei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, O\u2019Donnell School of Public Health, University of Texas Southwestern Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihir M","family":"Sanghvi","sequence":"additional","affiliation":[{"name":"Centre of Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, 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