This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2024 Oct 28:2024.10.25.24316158.

doi: 10.1101/2024.10.25.24316158.

Gene-Excessive Sleepiness Interactions Suggest Treatment Targets for Obstructive Sleep Apnea Subtype

Pavithra Nagarajan¹, Nuzulul Kurniansyah¹, Jiwon Lee¹, Sina A Gharib², Yushan Xu¹, Yiyan Zhang¹, Brian Spitzer¹, Tariq Faquih^{1

3}, Hufeng Zhou⁴, Eric Boerwinkle^{5

6}, Han Chen⁵, Daniel J Gottlieb^{1

7}, Xiuqing Guo⁸, Nancy L Heard-Costa^{9

10}, Bertha A Hidalgo¹¹, Daniel Levy^{10

12}, Peter Y Liu⁸, Hao Mei¹³, Rebecca Montalvan¹⁴, Sutapa Mukherjee^{15

16}, Kari E North¹⁷, George T O'Conner^{10

18}, Lyle J Palmer^{19

20}, Sanjay R Patel²¹, Bruce M Psaty^{22

23}, Shaun M Purcell^{3

24}, Laura M Raffield²⁵, Stephen S Rich^{26

27}, Jerome I Rotter⁸, Richa Saxena^{28

29}, Albert V Smith^{30

31}, Katie L Stone³², Xiaofeng Zhu³³; TOPMed Sleep Trait WG; Brian E Cade^{1

3}, Tamar Sofer^{1

34}, Susan Redline^{1

3}, Heming Wang^{1

3}

Affiliations

¹ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Pulmonary, Critical Care and Sleep Medicine, Medicine, University of Washington, Seattle, WA, USA.
³ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁷ Sleep Disorders Center, VA Boston Healthcare System.
⁸ The Institute for Translational Genomics and Population Sciences, Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts.
¹⁰ Framingham Heart Study, Framingham, Massachusetts, Boston, MA, USA.
¹¹ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
¹² Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
¹³ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁴ Westat, Rockville, Maryland, USA.
¹⁵ Adelaide Institute for Sleep Health / Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia.
¹⁶ Sleep Health Service, Respiratory and Sleep Service, Southern Adelaide Local Health Network, Bedford Park, South Australia, Australia.
¹⁷ Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁸ Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹⁹ Australian Institute for Machine Learning, University of Adelaide, Adelaide, SA, Australia.
²⁰ School of Public Health, University of Adelaide, Adelaide, SA, Australia.
²¹ Center for Sleep and Cardiovascular Outcomes Research, University of Pittsburgh, Pittsburgh, PA, USA.
²² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²³ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁴ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁵ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
²⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁷ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
²⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³¹ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³² California Pacific Medical Center Research Institute, San Francisco and Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.
³³ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
³⁴ CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.

PMID: 39574859
PMCID: PMC11581070
DOI: 10.1101/2024.10.25.24316158

Gene-Excessive Sleepiness Interactions Suggest Treatment Targets for Obstructive Sleep Apnea Subtype

Pavithra Nagarajan et al. medRxiv. 2024.

[Preprint]. 2024 Oct 28:2024.10.25.24316158.

doi: 10.1101/2024.10.25.24316158.

Authors

Affiliations

¹ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Pulmonary, Critical Care and Sleep Medicine, Medicine, University of Washington, Seattle, WA, USA.
³ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁷ Sleep Disorders Center, VA Boston Healthcare System.
⁸ The Institute for Translational Genomics and Population Sciences, Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts.
¹⁰ Framingham Heart Study, Framingham, Massachusetts, Boston, MA, USA.
¹¹ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
¹² Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
¹³ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁴ Westat, Rockville, Maryland, USA.
¹⁵ Adelaide Institute for Sleep Health / Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia.
¹⁶ Sleep Health Service, Respiratory and Sleep Service, Southern Adelaide Local Health Network, Bedford Park, South Australia, Australia.
¹⁷ Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁸ Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹⁹ Australian Institute for Machine Learning, University of Adelaide, Adelaide, SA, Australia.
²⁰ School of Public Health, University of Adelaide, Adelaide, SA, Australia.
²¹ Center for Sleep and Cardiovascular Outcomes Research, University of Pittsburgh, Pittsburgh, PA, USA.
²² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²³ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁴ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁵ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
²⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁷ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
²⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³¹ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³² California Pacific Medical Center Research Institute, San Francisco and Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.
³³ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
³⁴ CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.

PMID: 39574859
PMCID: PMC11581070
DOI: 10.1101/2024.10.25.24316158

Abstract

Obstructive sleep apnea (OSA) is a multifactorial sleep disorder characterized by a strong genetic basis. Excessive daytime sleepiness (EDS) is a symptom that is reported by a subset of OSA patients, persisting even after treatment with continuous positive airway pressure (CPAP). It is recognized as a clinical subtype underlying OSA carrying alarming heightened cardiovascular risk. Thus, conceptualizing EDS as an exposure variable, we sought to investigate EDS's influence on genetic variation linked to apnea-hypopnea index (AHI), a diagnostic measure of OSA severity. This study serves as the first large-scale genome-wide gene x environment interaction analysis for AHI, investigating the interplay between its genetic markers and EDS across and within specific sex. Our work pools together whole genome sequencing data from seven cohorts, enabling a diverse dataset (four population backgrounds) of over 11,500 samples. Among the total 16 discovered genetic targets with interaction evidence with EDS, eight are previously unreported for OSA, including CCDC3, MARCHF1, and MED31 identified in all sexes; TMEM26, CPSF4L, and PI4K2B identified in males; and RAP1GAP and YY1 identified in females. We discuss connections to insulin resistance, thiamine deficiency, and resveratrol use that may be worthy of therapeutic consideration for excessively sleepy OSA patients.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: LMR is a consultant for the TOPMed Administrative Coordinating Center (through Westat).

Figures

**Figure 1.**
Overall conceptual workflow of this study.

**Figure 2.**
Common variant x EDS interaction effect on AHI. A. Manhattan plot of 1df G×E interaction effect. Two common genetic variants are significant at the genome-wide level (p<5e-08) –rs13118183 (MARCHF1) and rs281851 (CCDC3) – for their interaction effect with EDS. B. Forest plot of rs13118183 (MARCHF1) association with AHI in EDS and non-EDS groups, stratified by sex. C. Forest plot of rs281851 (CCDC3) association with AHI in EDS and non-EDS groups, stratified by sex.

See this image and copyright information in PMC

References

1. Redline S., Azarbarzin A. & Peker Y. Obstructive sleep apnoea heterogeneity and cardiovascular disease. Nat Rev Cardiol 20, 560–573 (2023). - PubMed
1. Szily M. et al. Genetic influences on the onset of obstructive sleep apnoea and daytime sleepiness: a twin study. Respir Res 20, 125 (2019). - PMC - PubMed
1. Sofer T. et al. Genome-wide association study of obstructive sleep apnoea in the Million Veteran Program uncovers genetic heterogeneity by sex. EBioMedicine 90, 104536 (2023). - PMC - PubMed
1. Rosenberg R., Schweitzer P.K., Steier J. & Pepin J.L. Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management. Postgrad Med 133, 772–783 (2021). - PubMed
1. Lal C., Weaver T.E., Bae C.J. & Strohl K.P. Excessive Daytime Sleepiness in Obstructive Sleep Apnea. Mechanisms and Clinical Management. Ann Am Thorac Soc 18, 757–768 (2021). - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

This is a preprint.

Gene-Excessive Sleepiness Interactions Suggest Treatment Targets for Obstructive Sleep Apnea Subtype

Affiliations

Gene-Excessive Sleepiness Interactions Suggest Treatment Targets for Obstructive Sleep Apnea Subtype

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources