Gene-by-Sleep Duration Interaction for Glycemic Traits in More Than 480,000 Individuals

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the current 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—6 with short sleep and 10 with long sleep. Of these, four loci were identified through cross-population meta-analysis. Mapped genes exhibited pathway connections to pericyte apoptosis, N-methyl-d-aspartate receptor activity, the GLUT1 receptor, neurological health, and sleep architecture. Eleven loci (VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, and MAPT) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identified 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. Article Highlights The biological mechanisms of how sleep duration impacts type 2 diabetes pathogenesis and glycemic control are unclear. 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 nonoverlapping. Regulation of copper and diacylglycerol levels appear as distinct cellular mechanisms implicated by long and short sleep duration loci, respectively. Identified gene targets present insight for potential type 2 diabetes therapeutic design approaches related to JIP1–c-Jun N-terminal kinase interaction disruption, pericyte health, N-methyl-d-aspartate receptor activity, anti-inflammatory and leptin-enhancing dietary supplements, and serpins.

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Journal
Diabetes
Published
2026-10-29
DOI
https://doi.org/10.2337/db26-0184
Primary Topic
Genetic Associations and Epidemiology
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article
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article

Gene-by-Sleep Duration Interaction for Glycemic Traits in More Than 480,000 Individuals

Vilmundur G. Gudnason, Traci M. Bartz, Valborg Guðmundsdóttir, Sandy FinesilverSmith et al.
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Diabetes
Genetic Associations and Epidemiology
article

Gene-by-Sleep Duration Interaction for Glycemic Traits in More Than 480,000 Individuals

Vilmundur G. Gudnason, Traci M. Bartz, Valborg Guðmundsdóttir, Sandy FinesilverSmith, Clint L. Miller, John L. Morrison, Nora Franceschini, Rozenn N. Lemaître, Ilja Maria Nolte, Amanda M. Fretts, Alexis C. Wood, Renata Ludmila Riha, Christophe M. Lefèvre, Rodney John Scott, Raymond Noordam, Pramod Anugu, Anne Richmond, Diana Dunca, Lenore J. Launer, Brian E. Cade, Mark O. Goodarzi, Chenglong Yu, Susan P. Fisher‐Hoch, Julia Ramírez, YUJIE WANG, Jian’an Luan, Celestin Missikpode, Jennifer Elizabeth Below, Amy R. Bentley, Sarah Elizabeth Harris, Tamar Sofer, Archie I Campbell, Mary Furlan Feitosa, Hugues Aschard, Tariq O. Faquih, Hans Jörgen Grabe, Kristin L. Young, Kenneth E. Westerman, Minjung Kho, Laura M. Raffield, Jeffrey R. O’Connell, Miranda T. Schram, Mika A. P. Kähönen, Caroline Hayward, Sarah C Hsu, Timo Antero Lakka, Tom C. Russ, Peter J. van der Most, Lorenz Risch, Mariaelisa Graff, Lydia Bazzano, Kaavya Ashok, Pavithra Nagarajan, John Attia, James E. Hixson, Quan Sun, John J. McNeil, Olli Tuomas Raitakari, Md Abu Yusuf Ansari, Yipei Song, Mohsen Ghanbari, David Conen, Sami Heikkinen, Simon R. Cox, Michael R. Brown, Stefan Weiß, Latchezar M. Dimitrov, Leo‐Pekka Lyytikäinen, Sina A. Gharib, Martin Risch, Uwe Völker, Mihir M. Sanghvi, Karen Schwander, Chloé Sarnowski, Heather M. Highland, C. Charles Gu, Mina Shahisavandi, Ruiyuan Zhang, Heming Wang, Jingxian Tang, Joseph McCormick, Paul Hanson, Ervin Ray Fox, Henry Völzke, Pirjo Komulainen, Aldi T. Kraja, Nicholette D. Palmer, Vincent Braunack-Mayer, Zhijie Huang, Hyunju Kim, Changhoon Kang, Jiawen Du, Jiang He, Changwei Li, Xiuqing Guo, Xiaofeng Zhu (36670), Ko Willems van Dijk, Wanying Zhu, Ling Chen, Anh Do
article en

Abstract

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the current 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—6 with short sleep and 10 with long sleep. Of these, four loci were identified through cross-population meta-analysis. Mapped genes exhibited pathway connections to pericyte apoptosis, N-methyl-d-aspartate receptor activity, the GLUT1 receptor, neurological health, and sleep architecture. Eleven loci (VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, and MAPT) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identified 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. Article Highlights The biological mechanisms of how sleep duration impacts type 2 diabetes pathogenesis and glycemic control are unclear. 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 nonoverlapping. Regulation of copper and diacylglycerol levels appear as distinct cellular mechanisms implicated by long and short sleep duration loci, respectively. Identified gene targets present insight for potential type 2 diabetes therapeutic design approaches related to JIP1–c-Jun N-terminal kinase interaction disruption, pericyte health, N-methyl-d-aspartate receptor activity, anti-inflammatory and leptin-enhancing dietary supplements, and serpins.

Diabetes
Broad Institute (US), Boston University (US), University of North Carolina at Chapel Hill (US), Tulane University (US), University of Southern California (US), University of Bern (CH), University of Maryland, Baltimore (US), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), National Institutes of Health (US), Beth Israel Deaconess Medical Center (US), University Medical Center Groningen (NL), Children's Hospital of Philadelphia (US), Harvard University (US), Seoul National University (KR), Tampere University of Applied Sciences (FI), University of Turku (FI), Institut Pasteur (FR), University of Iceland (IS), Queen Mary University of London (GB), Tampere University (FI), University of Groningen (NL), University of Eastern Finland (FI), The Lundquist Institute (US), Baylor College of Medicine (US), Vanderbilt University (US), University of Washington (US), Washington University in St. Louis (US), Université Paris Cité (FR), Barts Health NHS Trust (GB), University of Cambridge (GB), Universidad de Zaragoza (ES), Universitätsmedizin Greifswald (DE), Leiden University Medical Center (NL), University Hospital of Bern (CH), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), Turku University Hospital (FI), Population Health Research Institute (CA), University of Mississippi Medical Center (US), Universität Greifswald (DE), University of Illinois Chicago (US), Massachusetts General Hospital (US), National Human Genome Research Institute (US), Kuopio University Hospital (FI), Private University in the Principality of Liechtenstein (LI), Tampere University Hospital (FI), German Centre for Cardiovascular Research (DE), Tampere University (FI), Fimlab (Finland) (FI), National Institute on Aging (US), Children's Nutrition Research Center at Baylor College of Medicine (US), Kantonsspital Graubünden (CH), William Harvey Research Institute (GB), Icelandic Heart Association (IS), MRC Epidemiology Unit (GB), Institute of Genetics and Cancer (GB), Harbor–UCLA Medical Center (US), University of Tampere (FI), Diabetes Center Berne (CH), Instituto de Investigación en Ingeniería de Aragón (ES), Wake Forest University Health Sciences (US), Wake Forest University (US), University of Virginia (US), Monash University (AU), Case Western Reserve University (US), University of Newcastle Australia (AU), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US), Erasmus University Rotterdam (NL), The University of Texas Health Science Center at Houston (US), McMaster University (CA), University of Edinburgh (GB)
U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute on Minority Health and Health Disparities
Good health and well-being
Openalex Percentile: Top 15%
Genetic Associations and Epidemiology
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