Meta-Analysis

. 2026 Jan:412:120603.

doi: 10.1016/j.atherosclerosis.2025.120603. Epub 2025 Nov 26.

Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

Raymond Noordam¹, Wenyi Wang², Pavithra Nagarajan³, Heming Wang⁴, Michael R Brown⁵, Amy R Bentley⁶, Qin Hui⁷, Aldi T Kraja⁸, John L Morrison⁹, Jeffrey R O'Connel¹⁰, Songmi Lee¹¹, Karen Schwander¹², Traci M Bartz¹³, Lisa de Las Fuentes¹⁴, Mary F Feitosa¹⁵, Xiuqing Guo¹⁶, Xu Hanfei¹⁷, Sarah E Harris¹⁸, Zhijie Huang¹⁹, Mart Kals²⁰, Christophe Lefevre²¹, Massimo Mangino²², Yuri Milaneschi²³, Peter J van der Most²⁴, Natasha L Pacheco²⁵, Nicholette D Palmer²⁶, Varun Rao²⁷, Rainer Rauramaa²⁸, Quan Sun²⁹, Yasuharu Tabara³⁰, Dina Vojinovic³¹, Yujie Wang³², Stefan Weiss³³, Qian Yang³⁴, Wei Zhao³⁵, Wanying Zhu³⁶, Md Abu Yusuf Ansari³⁷, Hugues Aschard³⁸, Pramod Anugu³⁹, Themistocles L Assimes⁴⁰, John Attia⁴¹, Laura D Baker⁴², Christie Ballantyne⁴³, Lydia Bazzano¹⁹, Eric Boerwinkle⁴⁴, Brain Cade⁴, Hung-Hsin Chen³⁶, Wei Chen¹⁹, Yii-Der Ida Chen¹⁷, Zekai Chen²⁴, Kelly Cho⁴⁵, Ileana De Anda-Duran¹⁹, Latchezar Dimitrov²⁶, Anh Do⁴⁶, Todd Edwards⁴⁷, Tariq Faquih⁴, Aroon Hingorani⁴⁸, Susan P Fisher-Hoch⁴⁹, J Michael Gaziano⁴⁵, Sina A Gharib⁵⁰, Ayush Giri⁵¹, Mohsen Ghanbari³¹, Hans Jörgen Grabe⁵², Mariaelisa Graff³², C Charles Gu⁴⁶, Jiang He¹⁹, Sami Heikkinen⁵³, James Hixson⁵⁴, Yuk-Lam Ho⁵⁵, Michelle M Hood⁵⁶, Serena C Houghton⁵⁵, Carrie A Karvonen-Gutierrez⁵⁶, Takahisa Kawaguchi⁵⁷, Tuomas O Kilpeläinen⁵⁸, Pirjo Komulainen²⁸, Henry J Lin¹⁶, Gregorio V Linchangco Jr⁵⁹, Annemarie I Luik³¹, Jintao Ma⁶⁰, James B Meigs⁶¹, Joseph B McCormick⁴⁹, Cristina Menni²², Ilja M Nolte²⁴, Jill M Norris⁶², Lauren E Petty³⁶, Hannah G Polikowsky³⁶, Laura M Raffield⁶³, Stephen S Rich⁶⁴, Renata L Riha⁶⁵, Thomas C Russ⁶⁶, Edward A Ruiz-Narvaez⁶⁷, Colleen M Sitlani⁶⁸, Jennifer A Smith³⁵, Harold Snieder²⁴, Tamar Sofer⁶⁹, Botong Shen²⁵, Jingxian Tang¹⁷, Kent D Taylor⁷⁰, Maris Teder-Laving²⁰, Rima Triatin⁷¹, Michael Y Tsai⁷², Henry Völzke⁷³, Kenneth E Westerman⁷⁴, Rui Xia¹¹, Jie Yao¹⁶, Kristin L Young³², Ruiyuan Zhang¹⁹, Alan B Zonderman²⁵, Xiaofeng Zhu⁷⁵, Jennifer E Below³⁶, Simon R Cox¹⁸, Michelle Evans²⁵, Myriam Fornage⁷⁶, Ervin R Fox⁷⁷, Nora Franceschini⁷⁸, Sioban D Harlow⁵⁶, Elizabeth Holliday⁴¹, M Arfan Ikram³¹, Tanika Kelly²⁷, Timo A Lakka⁷⁹, Deborah A Lawlor³⁴, Changwei Li¹², Ching-Ti Liu¹⁹, Reedik Mägi²⁰, Alisa K Manning⁸⁰, Fumihiko Matsuda⁵⁷, Alanna C Morrison⁵, Matthias Nauck⁸¹, Kari E North³², Brenda Wjh Penninx²³, Michael A Province¹², Bruce M Psaty⁸², Jerome I Rotter¹⁶, Tim D Spector⁸³, Lynne E Wagenknecht⁸⁴, Ko Willems van Dijk⁸⁵; Lifelines Cohort Study⁸⁶; Million Veteran Program; Cashell E Jaquish⁸⁷, Peter Wf Wilson⁵⁹, Patricia A Peyser⁵⁶, Patricia B Munroe⁸⁸, Paul S de Vries⁵, W James Gauderman⁹, Yan V Sun⁵⁹, Han Chen⁵, Clint L Miller⁸⁹, Thomas W Winkler⁹⁰, Dabeeru C Rao⁴⁶, Susan Redline⁴, Diana van Heemst⁹¹

Affiliations

¹ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; Health Campus the Hague/Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: r.noordam@lumc.nl.
² Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
³ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁵ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
⁶ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Rollins School of Public Health, Department of Epidemiology, Emory University, Atlanta, GA, USA.
⁸ University of Mississippi Medical Center, Jackson, MS, USA.
⁹ Divison of Biostatistics and Health Data Science, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁰ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹ Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
¹² Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹³ Cardiovascular Health Research Unit, Department of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
¹⁴ Center for Biostatistics and Data Science, Institute for Informatics, Data Science and Biostatistics, Washington University in St. Louis, St. Louis, Missouri, USA; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁵ Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁶ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁷ Department of Biostatistics, Boston University, Boston, MA, USA.
¹⁸ Lothian Birth Cohorts, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
¹⁹ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
²⁰ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
²¹ Department of Bioinformatics, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
²² Department of Twin Research, King's College London, London, UK.
²³ GGZ inGeest, Amsterdam, the Netherlands; Department of Psychiatry, Amsterdam UMC/Vrije universiteit, Amsterdam, the Netherlands.
²⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁵ National Institute on Aging, Laboratory of Epidemiology and Population Sciences, National Institutes of Health, Baltimore, MD, USA.
²⁶ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
²⁷ Division of Nephrology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
²⁸ Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
²⁹ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁰ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan.
³¹ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
³² Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
³³ Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greiswald, Germany.
³⁴ MRC Integrative Epidemiology Unit at then University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA; Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
³⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁷ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
³⁸ Institut Pasteur, Université Paris Cité, Department of Computational Biology, F-75015 Paris, France; Department of Epidemiology, Harvard TH School of Public Health, Boston, MA, 2115, USA.
³⁹ Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁰ Division of Cardiology, Department of Medicine, Palo Alto VA Healthcare System, Palo Alta, CA, USA; Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA, USA.
⁴¹ School of Medicine and Public Health, University of Newcastle, New Lambton Heights, Australia.
⁴² Department of Internal Medicine (Geriatrics & Gerontology), Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁴³ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁴⁴ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁴⁵ Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Veterans Affairs Boston Healthcare System, Boston, MA, USA.
⁴⁶ Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University in St. Louis, School of Medicine, St. Louis, MO, 63110, USA.
⁴⁷ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.
⁴⁸ Faculty of Population Health, Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK.
⁴⁹ School of Public Health, The University of Texas Health Science Center at Houston (UTHealth), Brownsville, TX, USA.
⁵⁰ Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
⁵¹ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37203, USA; Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵² Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases, Site Rostock/Greifswald, Greifswald, Germany.
⁵³ Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.
⁵⁴ Department of Epidemiology, UTHealth School of Public Health, Houston TX, USA.
⁵⁵ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Veterans Affairs Boston Healthcare System, Boston, MA, USA.
⁵⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁵⁷ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁵⁸ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, 2142, USA.
⁵⁹ Rollins School of Public Health, Department of Epidemiology, Emory University, Atlanta, GA, USA; Veterans Affairs Atlanta Healthcare System, Decatur, GA, USA.
⁶⁰ Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, 2111, USA.
⁶¹ Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of General Internal Medicine, Massachusetts General Hospital, 100 Cambridge St 16th Floor, Boston, MA, USA.
⁶² Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
⁶³ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁶⁴ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁶⁵ Department of Sleep Medicine, The University of Edinburgh, Edinburgh, UK.
⁶⁶ Alzheimer Scotland, Dementia Research Centre, The University of Edinburgh, Edinburgh, UK; Division of Psychiatry, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
⁶⁷ Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁶⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶⁹ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; CardioVascular Institute (CVI), Beth Israel Deaconness Medical Center, Boston, MA, USA.
⁷⁰ Division of Genomic Outcomes, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Biomedical Sciences, Universitas Padjadjaran, Bandung, Indonesia.
⁷² Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁷³ DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greiswald, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁷⁴ Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Medicine, Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, USA.
⁷⁵ Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
⁷⁶ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
⁷⁷ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁷⁸ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷⁹ Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
⁸⁰ Massachusetts General Hospital, Clinical and Translational Epidemiology Unit, Department of Medicine, Boston, MA, 02114, USA; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁸¹ DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greiswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁸² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁸³ GGZ inGeest, Amsterdam, the Netherlands.
⁸⁴ Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁸⁵ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
⁸⁶ Roden, the Netherlands.
⁸⁷ Division of Cardiovascular Science, Epidemiology Branch, NHLBI, NIH, Bethesda, MD, 20817, USA.
⁸⁸ William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK; National Institute of Health and Care Research Barts Biomedical Research Centre, Queen Mary University of London, London, UK.
⁸⁹ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908, USA.
⁹⁰ Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
⁹¹ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

PMID: 41325697
PMCID: PMC12757440
DOI: 10.1016/j.atherosclerosis.2025.120603

Meta-Analysis

Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

Raymond Noordam et al. Atherosclerosis. 2026 Jan.

. 2026 Jan:412:120603.

doi: 10.1016/j.atherosclerosis.2025.120603. Epub 2025 Nov 26.

Authors

Affiliations

¹ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; Health Campus the Hague/Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: r.noordam@lumc.nl.
² Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
³ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁵ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
⁶ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Rollins School of Public Health, Department of Epidemiology, Emory University, Atlanta, GA, USA.
⁸ University of Mississippi Medical Center, Jackson, MS, USA.
⁹ Divison of Biostatistics and Health Data Science, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁰ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹ Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
¹² Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹³ Cardiovascular Health Research Unit, Department of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
¹⁴ Center for Biostatistics and Data Science, Institute for Informatics, Data Science and Biostatistics, Washington University in St. Louis, St. Louis, Missouri, USA; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁵ Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁶ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁷ Department of Biostatistics, Boston University, Boston, MA, USA.
¹⁸ Lothian Birth Cohorts, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
¹⁹ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
²⁰ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
²¹ Department of Bioinformatics, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
²² Department of Twin Research, King's College London, London, UK.
²³ GGZ inGeest, Amsterdam, the Netherlands; Department of Psychiatry, Amsterdam UMC/Vrije universiteit, Amsterdam, the Netherlands.
²⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁵ National Institute on Aging, Laboratory of Epidemiology and Population Sciences, National Institutes of Health, Baltimore, MD, USA.
²⁶ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
²⁷ Division of Nephrology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
²⁸ Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
²⁹ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁰ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan.
³¹ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
³² Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
³³ Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greiswald, Germany.
³⁴ MRC Integrative Epidemiology Unit at then University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA; Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
³⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁷ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
³⁸ Institut Pasteur, Université Paris Cité, Department of Computational Biology, F-75015 Paris, France; Department of Epidemiology, Harvard TH School of Public Health, Boston, MA, 2115, USA.
³⁹ Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁰ Division of Cardiology, Department of Medicine, Palo Alto VA Healthcare System, Palo Alta, CA, USA; Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA, USA.
⁴¹ School of Medicine and Public Health, University of Newcastle, New Lambton Heights, Australia.
⁴² Department of Internal Medicine (Geriatrics & Gerontology), Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁴³ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁴⁴ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁴⁵ Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Veterans Affairs Boston Healthcare System, Boston, MA, USA.
⁴⁶ Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University in St. Louis, School of Medicine, St. Louis, MO, 63110, USA.
⁴⁷ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.
⁴⁸ Faculty of Population Health, Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK.
⁴⁹ School of Public Health, The University of Texas Health Science Center at Houston (UTHealth), Brownsville, TX, USA.
⁵⁰ Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
⁵¹ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37203, USA; Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵² Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases, Site Rostock/Greifswald, Greifswald, Germany.
⁵³ Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.
⁵⁴ Department of Epidemiology, UTHealth School of Public Health, Houston TX, USA.
⁵⁵ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Veterans Affairs Boston Healthcare System, Boston, MA, USA.
⁵⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁵⁷ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁵⁸ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, 2142, USA.
⁵⁹ Rollins School of Public Health, Department of Epidemiology, Emory University, Atlanta, GA, USA; Veterans Affairs Atlanta Healthcare System, Decatur, GA, USA.
⁶⁰ Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, 2111, USA.
⁶¹ Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of General Internal Medicine, Massachusetts General Hospital, 100 Cambridge St 16th Floor, Boston, MA, USA.
⁶² Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
⁶³ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁶⁴ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁶⁵ Department of Sleep Medicine, The University of Edinburgh, Edinburgh, UK.
⁶⁶ Alzheimer Scotland, Dementia Research Centre, The University of Edinburgh, Edinburgh, UK; Division of Psychiatry, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
⁶⁷ Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁶⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶⁹ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; CardioVascular Institute (CVI), Beth Israel Deaconness Medical Center, Boston, MA, USA.
⁷⁰ Division of Genomic Outcomes, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Biomedical Sciences, Universitas Padjadjaran, Bandung, Indonesia.
⁷² Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁷³ DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greiswald, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁷⁴ Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Medicine, Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, USA.
⁷⁵ Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
⁷⁶ Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
⁷⁷ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁷⁸ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷⁹ Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
⁸⁰ Massachusetts General Hospital, Clinical and Translational Epidemiology Unit, Department of Medicine, Boston, MA, 02114, USA; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁸¹ DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greiswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁸² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁸³ GGZ inGeest, Amsterdam, the Netherlands.
⁸⁴ Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁸⁵ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
⁸⁶ Roden, the Netherlands.
⁸⁷ Division of Cardiovascular Science, Epidemiology Branch, NHLBI, NIH, Bethesda, MD, 20817, USA.
⁸⁸ William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK; National Institute of Health and Care Research Barts Biomedical Research Centre, Queen Mary University of London, London, UK.
⁸⁹ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908, USA.
⁹⁰ Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
⁹¹ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

PMID: 41325697
PMCID: PMC12757440
DOI: 10.1016/j.atherosclerosis.2025.120603

Abstract

Background and aims: Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets.

Methods: We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels.

Results: The one-degree of freedom variant-sleep interaction test identified 10 novel loci (P_int<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (P_joint<5.0e-9 in combination with P_int<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature.

Conclusions: Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

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Conflict of interest statement

Declaration of competing interest HJG has received travel grants and speakers honoraria from Neuraxpharm, Servier, Indorsia and Janssen Cilag. LMR is a consultant for the TOPMed Administrative Coordinating Center (through Westat). TDS is co-founder and shareholder of ZOE Ltd. HC receives consulting fees from Character Biosciences. All other co-authors declare to have no conflicts of interest.

Figures

**Figure 1:**
Study design and analytical pipeline of the project.

**Figure 2:. Circular -log10(Pint) plot of all the 6 main analyses in the cross-population meta-analysis of men and women combined.**
ASPH (TG and LTST) maps also at the *CLVS1* locus.

**Figure 3:. Main results from the 1-degree of freedom interaction analyses in different subgroups.**
Presented results are the additive variant-interaction effects (log units for TG and HDL-c; mg/dL). Only variants passing all post meta-analysis QC steps were presented. Abbreviations: HDL-c, high-density lipoprotein cholesterol. LDL-c, low-density lipoprotein cholesterol; LTST, long total sleep time; STST, short total sleep time; TG, triglycerides.

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References

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R01 HL153814/HL/NHLBI NIH HHS/United States

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Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

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Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants

Authors

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Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous