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[Preprint]. 2024 Jul 17:rs.3.rs-4163414.

doi: 10.21203/rs.3.rs-4163414/v1.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations

Heming Wang¹, Pavithra Nagarajan, Thomas Winkler, Amy Bentley², Clint Miller, Aldi Kraja, Karen Schwander, Songmi Lee, Wenyi Wang, Michael Brown³, John Morrison, Ayush Giri, Jeffrey O'Connell, Traci Bartz, Lisa de Las Fuentes⁴, Valborg Gudmundsdottir, Xiuqing Guo⁵, Sarah Harris⁶, Zhijie Huang, Mart Kals, Minjung Kho, Christophe Lefevre, Jian'an Luan⁷, Leo-Pekka Lyytikäinen⁸, Massimo Mangino⁹, Y Milaneschi¹⁰, Nicholette Palmer¹¹, Varun Rao, Rainer Rauramaa, Botong Shen, Stefan Stadler, Quan Sun¹², Jingxian Tang, Sébastien Thériault, Adriaan van der Graaf, Peter van der Most, Yujie Wang, Stefan Weiss¹³, Kenneth Westerman, Qian Yang, Tabara Yasuharu, Wei Zhao¹⁴, Wanying Zhu, Drew Altschul, Md Abu Yusuf Ansari, Pramod Anugu, Anna Argoty-Pantoja, Michael Arzt, Hugues Aschard¹⁵, John Attia, Lydia Bazzano¹⁶, Max Breyer, Jennifer Brody, Brian Cade¹, Hung-Hsin Chen¹⁷, Yii-Der Ida Chen, Zekai Chen, Paul de Vries¹⁸, Latchezar Dimitrov, Ahn Do, Jiawen Du, Charles Dupont, Todd Edwards, Michele Evans¹⁹, Tariq Faquih, Stephan Felix, Susan Fisher-Hoch, James Floyd, Mariaelisa Graff²⁰, C Charles Gu²¹, Dongfeng Gu, Kristen Hairston, Anthony Hanley, Iris Heid²², Sami Heikkinen²³, Heather Highland²⁴, Michelle Hood, Mika Kähönen²⁵, Carrie Karvonen-Gutierrez, Takahisa Kawaguchi, Setoh Kazuya, Kelly Tanika²⁶, Pirjo Komulainen, Daniel Levy, Henry Lin, Peter Liu, Pedro Marques-Vidal, Joseph McCormick²⁷, Hao Mei²⁸, James Meigs, Cristina Menni⁹, Kisung Nam²⁹, Ilja Nolte³⁰, Natasha Pacheco, Lauren Petty, Hannah Polikowsky, Michael Province²¹, Bruce Psaty³¹, Laura Raffield, Olli Raitakari³², Stephen Rich³³, Renata Riha, Lorenz Risch, Martin Risch, Edward Ruiz-Narvaez, Rodney Scott³⁴, Colleen Sitlani, Jennifer Smith¹⁴, Tamar Sofer³⁵, Maris Teder-Laving, Uwe Völker³⁶, Peter Vollenweider³⁷, Guanchao Wang, Ko WIllems van Dijk³⁸, Otis Wilson, Rui Xia³⁹, Jie Yao, Kristin Young, Ruiyuan Zhang, Xiaofeng Zhu⁴⁰, Jennifer Below¹⁷, Carsten Böger, David Conen, Simon Cox⁴¹, Marcus Dörr³⁶, Mary Feitosa⁴, Ervin Fox, Nora Franceschini, Sina Gharib⁴², Vilmundur Gudnason⁴³, Sioban Harlow, Jiang He⁴⁴, Elizabeth Holliday⁴⁵, Zoltan Kutalik, Timo Lakka, Deborah Lawlor⁴⁶, Seunggeun Lee, Terho Lehtimäki⁴⁷, Changwei Li⁴⁸, Ching-Ti Liu⁴⁹, Reedik Mägi, Fumihiko Matsuda, Alanna Morrison³, Brenda W J H Penninx, Patricia Peyser⁵⁰, Jerome Rotter⁵¹, Harold Snieder⁵², T Spector, Lynne Wagenknecht, Nicholas Wareham⁷, Alan Zonderman⁵³, Kari North⁵⁴, Myriam Fornage^{55

56}, Adriana Hung, Alisa Manning, W Gauderman, Han Chen, Patricia Munroe, Dabeeru Rao⁵⁷, Diana van Heemst, Susan Redline¹, Raymond Noordam³⁸

Affiliations

¹ Brigham and Women's Hospital.
² National Institutes of Health, NHGRI.
³ The University of Texas Health Science Center at Houston.
⁴ Washington University School of Medicine.
⁵ The Lundquist Institute.
⁶ The University of Edinburgh.
⁷ University of Cambridge.
⁸ Fimlab Laboratories and Finnish Cardiovascular Research Center.
⁹ King's College London.
¹⁰ VU University Medical Center.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai.
¹² University of North Carolina, USA.
¹³ University Medicine Greifswald & University of Greifswald.
¹⁴ University of Michigan.
¹⁵ Institut Pasteur.
¹⁶ Louisiana State University.
¹⁷ Vanderbilt University Medical Center.
¹⁸ Human Genetics Center.
¹⁹ National Institute on Aging.
²⁰ University of North Carolina.
²¹ Washington University.
²² University of Regensburg.
²³ Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus.
²⁴ University of North Carolina at Chapel Hill.
²⁵ Tampere University.
²⁶ University of Illinois Chicago.
²⁷ The University of Texas Health Science Center at Houston (UTHealth) School of Public Health.
²⁸ University of Mississippi Medical Center.
²⁹ Seoul National University.
³⁰ University of Groningen, University Medical Center Groningen.
³¹ Cardiovascular Health Research Unit.
³² Turku University Hospital and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku.
³³ University of Virginia.
³⁴ University of Newcastle and the Hunter Medical Research Institute.
³⁵ Harvard University.
³⁶ University Medicine Greifswald.
³⁷ Lausanne University Hospital (CHUV).
³⁸ Leiden University Medical Center.
³⁹ The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston.
⁴⁰ Case Western Reserve University.
⁴¹ University of Edinburgh.
⁴² University of Washington.
⁴³ Icelandic Heart Association.
⁴⁴ Tulane University School of Public Health and Tropical Medicine.
⁴⁵ Hunter Medical Research Institute.
⁴⁶ University of Bristol.
⁴⁷ Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University.
⁴⁸ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
⁴⁹ Boston University School of Public Health.
⁵⁰ Department of Epidemiology, School of Public Health, University of Michigan.
⁵¹ The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center.
⁵² University Medical Center Groningen.
⁵³ National Institute on Aging, NIA/NIH/IRP.
⁵⁴ UNC Chapel Hill.
⁵⁵ 1. Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center.
⁵⁶ 2. Human Genetics Center, Department of Epidemiology, School of Public Health.
⁵⁷ Washington University in St. Louis.

PMID: 39070651
PMCID: PMC11276021
DOI: 10.21203/rs.3.rs-4163414/v1

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations

Heming Wang et al. Res Sq. 2024.

[Preprint]. 2024 Jul 17:rs.3.rs-4163414.

doi: 10.21203/rs.3.rs-4163414/v1.

Authors

Affiliations

¹ Brigham and Women's Hospital.
² National Institutes of Health, NHGRI.
³ The University of Texas Health Science Center at Houston.
⁴ Washington University School of Medicine.
⁵ The Lundquist Institute.
⁶ The University of Edinburgh.
⁷ University of Cambridge.
⁸ Fimlab Laboratories and Finnish Cardiovascular Research Center.
⁹ King's College London.
¹⁰ VU University Medical Center.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai.
¹² University of North Carolina, USA.
¹³ University Medicine Greifswald & University of Greifswald.
¹⁴ University of Michigan.
¹⁵ Institut Pasteur.
¹⁶ Louisiana State University.
¹⁷ Vanderbilt University Medical Center.
¹⁸ Human Genetics Center.
¹⁹ National Institute on Aging.
²⁰ University of North Carolina.
²¹ Washington University.
²² University of Regensburg.
²³ Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus.
²⁴ University of North Carolina at Chapel Hill.
²⁵ Tampere University.
²⁶ University of Illinois Chicago.
²⁷ The University of Texas Health Science Center at Houston (UTHealth) School of Public Health.
²⁸ University of Mississippi Medical Center.
²⁹ Seoul National University.
³⁰ University of Groningen, University Medical Center Groningen.
³¹ Cardiovascular Health Research Unit.
³² Turku University Hospital and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku.
³³ University of Virginia.
³⁴ University of Newcastle and the Hunter Medical Research Institute.
³⁵ Harvard University.
³⁶ University Medicine Greifswald.
³⁷ Lausanne University Hospital (CHUV).
³⁸ Leiden University Medical Center.
³⁹ The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston.
⁴⁰ Case Western Reserve University.
⁴¹ University of Edinburgh.
⁴² University of Washington.
⁴³ Icelandic Heart Association.
⁴⁴ Tulane University School of Public Health and Tropical Medicine.
⁴⁵ Hunter Medical Research Institute.
⁴⁶ University of Bristol.
⁴⁷ Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University.
⁴⁸ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
⁴⁹ Boston University School of Public Health.
⁵⁰ Department of Epidemiology, School of Public Health, University of Michigan.
⁵¹ The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center.
⁵² University Medical Center Groningen.
⁵³ National Institute on Aging, NIA/NIH/IRP.
⁵⁴ UNC Chapel Hill.
⁵⁵ 1. Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center.
⁵⁶ 2. Human Genetics Center, Department of Epidemiology, School of Public Health.
⁵⁷ Washington University in St. Louis.

PMID: 39070651
PMCID: PMC11276021
DOI: 10.21203/rs.3.rs-4163414/v1

Update in

A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations.
Nagarajan P, Winkler TW, Bentley AR, Miller CL, Kraja AT, Schwander K, Lee S, Wang W, Brown MR, Morrison JL, Giri A, O'Connell JR, Bartz TM, de Las Fuentes L, Gudmundsdottir V, Guo X, Harris SE, Huang Z, Kals M, Kho M, Lefevre C, Luan J, Lyytikäinen LP, Mangino M, Milaneschi Y, Palmer ND, Rao V, Rauramaa R, Shen B, Stadler S, Sun Q, Tang J, Thériault S, van der Graaf A, van der Most PJ, Wang Y, Weiss S, Westerman KE, Yang Q, Yasuharu T, Zhao W, Zhu W, Altschul D, Ansari MAY, Anugu P, Argoty-Pantoja AD, Arzt M, Aschard H, Attia JR, Bazzanno L, Breyer MA, Brody JA, Cade BE, Chen HH, Chen YI, Chen Z, de Vries PS, Dimitrov LM, Do A, Du J, Dupont CT, Edwards TL, Evans MK, Faquih T, Felix SB, Fisher-Hoch SP, Floyd JS, Graff M, Gu C, Gu D, Hairston KG, Hanley AJ, Heid IM, Heikkinen S, Highland HM, Hood MM, Kähönen M, Karvonen-Gutierrez CA, Kawaguchi T, Kazuya S, Kelly TN, Komulainen P, Levy D, Lin HJ, Liu PY, Marques-Vidal P, McCormick JB, Mei H, Meigs JB, Menni C, Nam K, Nolte IM, Pacheco NL, Petty LE, Polikowsky HG, Province MA, Psaty BM, Raffield LM, Raitakari OT, Rich SS, Riha RL, Risch L, Risch M, Ruiz-Narvaez EA, Scott RJ, Sitlani CM, Smith JA, Sofer T, Teder-Laving M, Völker U, Vo… See abstract for full author list ➔ Nagarajan P, et al. Mol Psychiatry. 2025 Aug;30(8):3660-3672. doi: 10.1038/s41380-025-02954-w. Epub 2025 Apr 4. Mol Psychiatry. 2025. PMID: 40181193

Abstract

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

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Conflict of interest statement

Declarations CONFLICT OF INTEREST C.L.M. has received funding from AstraZeneca not related to the current study. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C. receives consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier. D.A.L. has received support from Medtronic LTD and Roche Diagnostics for biomarker research not related to the current study. The remaining authors declare no competing interests.

Figures

**Figure 2**
Forest Plots of Gene-Sleep Duration Loci Identified by the 1df Interaction Test in Female-Specific Cross-Population Meta-Analyses. These are the prioritized 1df Interaction Test results from female-specific cross-population meta-analyses. Contributing female-specific population groups’ (if this variant is found in the particular population group, after quality control) summary statistics are depicted here that were pooled.

**Figure 3**
Forest Plots of Gene-Sleep Duration Loci Identified by the 1df Interaction Test in Combined Sex HIS-Specific Meta-Analyses These are the prioritized 1df Interaction Test results from HIS-specific meta-analyses. Other population group data (if this variant is found in the particular population group, after quality control) are shown here to emphasize that these gene-sleep duration interaction loci were significant only in the HIS population group.

See this image and copyright information in PMC

References

1. Makarem N, Shechter A, Carnethon MR, Mullington JM, Hall MH, Abdalla M. Sleep Duration and Blood Pressure: Recent Advances and Future Directions. Curr Hypertens Rep. 2019;21(5):33. - PMC - PubMed
1. Kanki M, Nath AP, Xiang R, Yiallourou S, Fuller PJ, Cole TJ, et al. Poor sleep and shift work associate with increased blood pressure and inflammation in UK Biobank participants. Nat Commun. 2023;14(1):7096. - PMC - PubMed
1. Kario K. Sleep and nocturnal hypertension: Genes, environment, and individual profiles. J Clin Hypertens (Greenwich). 2022;24(10):1263–5. - PMC - PubMed
1. Bock JM, Vungarala S, Covassin N, Somers VK. Sleep Duration and Hypertension: Epidemiological Evidence and Underlying Mechanisms. Am J Hypertens. 2022;35(1):3–11. - PMC - PubMed
1. Matsubayashi H, Nagai M, Dote K, Turana Y, Siddique S, Chia YC, et al. Long sleep duration and cardiovascular disease: Associations with arterial stiffness and blood pressure variability. J Clin Hypertens (Greenwich). 2021;23(3):496–503. - PMC - PubMed

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This is a preprint.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations

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A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

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References

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