. 2026 Jan 13;49(1):zsaf212.

doi: 10.1093/sleep/zsaf212.

Genome-wide gene by sleepiness interaction analysis for sleep apnea

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'Connor^{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 Rich²⁶, Jerome I Rotter⁸, Richa Saxena^{27

28}, Albert V Smith^{29

30}, Katie L Stone³¹, Xiaofeng Zhu³²; TOPMed Sleep Trait Working Group; Brian E Cade^{1

3}, Tamar Sofer^{1

3

4

33}, Susan Redline^{1

3}, Heming Wang^{1

3}

Collaborators, Affiliations

Collaborators

TOPMed Sleep Trait Working Group:
Trevor Bierig, Brian Cade, Han Chen, Geetha Chittoor, Danielle Clarkson-Townsend, Daniel Cohen, Megan Duff, Joyita Dutta, Lynette Ekunwe, Tariq Faquih, Sina Gharib, Matthew Goodman, Daniel Gottlieb, Einat Granot-Hershkovitz, Lauren Hale, Scott Heemann, A J Hirsch Allen, Chao Agnes Hsiung, Tianyi Huang, Kuan-Yi Hung, Anne Justice, Brendan Keenan, Nataliia Kozhemiako, Jacqueline Lane, Xiang Li, Jingjing Liang, Diane Lim, Xihong Lin, Peter Liu, Jiayan Liu, Noah Lorincz-Comi, Faith Luyster, Matthew Maher, Yessie Martinez, Diego R Mazzotti, Hao Mei, Emmanuel Mignot, Miremad Moafi-Madani, Pavithra Nagarajan, Grace O'Brien, Jeff O'Connell, Heather Ochs-Balcom, Sanjay Patel, Shaun Purcell, Hira Qadir, Susan Redline, Michael Rueschman, Richa Saxena, Rachel Soemedi, Jae Hoon Sul, Shamil R Sunyaev, Cynthia Tchio, Daune Thorington, Heming Wang, Lluvia Xia, Jing Zhang, Grace Man Zhang, Ying Zhang, Hufeng Zhou, Xiaofeng Zhu

Affiliations

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

PMID: 40736211
PMCID: PMC12795742
DOI: 10.1093/sleep/zsaf212

Genome-wide gene by sleepiness interaction analysis for sleep apnea

Pavithra Nagarajan et al. Sleep. 2026.

. 2026 Jan 13;49(1):zsaf212.

doi: 10.1093/sleep/zsaf212.

Authors

Collaborators

TOPMed Sleep Trait Working Group:
Trevor Bierig, Brian Cade, Han Chen, Geetha Chittoor, Danielle Clarkson-Townsend, Daniel Cohen, Megan Duff, Joyita Dutta, Lynette Ekunwe, Tariq Faquih, Sina Gharib, Matthew Goodman, Daniel Gottlieb, Einat Granot-Hershkovitz, Lauren Hale, Scott Heemann, A J Hirsch Allen, Chao Agnes Hsiung, Tianyi Huang, Kuan-Yi Hung, Anne Justice, Brendan Keenan, Nataliia Kozhemiako, Jacqueline Lane, Xiang Li, Jingjing Liang, Diane Lim, Xihong Lin, Peter Liu, Jiayan Liu, Noah Lorincz-Comi, Faith Luyster, Matthew Maher, Yessie Martinez, Diego R Mazzotti, Hao Mei, Emmanuel Mignot, Miremad Moafi-Madani, Pavithra Nagarajan, Grace O'Brien, Jeff O'Connell, Heather Ochs-Balcom, Sanjay Patel, Shaun Purcell, Hira Qadir, Susan Redline, Michael Rueschman, Richa Saxena, Rachel Soemedi, Jae Hoon Sul, Shamil R Sunyaev, Cynthia Tchio, Daune Thorington, Heming Wang, Lluvia Xia, Jing Zhang, Grace Man Zhang, Ying Zhang, Hufeng Zhou, Xiaofeng Zhu

Affiliations

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

PMID: 40736211
PMCID: PMC12795742
DOI: 10.1093/sleep/zsaf212

Abstract

Study objectives: Excessive daytime sleepiness (EDS), influenced by environmental and social-behavioral factors, is reported by a subset of patients with sleep apnea-a group that may be at elevated cardiovascular risk. However, it is unclear whether sleep apnea with and without EDS have distinct genetic underpinnings. In this study, we perform gene-by-EDS interaction analyses for apnea hypopnea index, a diagnostic marker of sleep apnea severity, to understand EDS's influence on its underlying genetic risk.

Methods: Discovery interaction analyses for common variants and gene-based rare variants were conducted respectively using multi-ethnic Trans-Omics for Precision Medicine (N = 11 619) data, followed by replication and subsequent meta-analysis in additional Trans-Omics for Precision Medicine-imputed data (N = 8904). The 1 degree-of-freedom (1df) G × E test and the 2df joint G,G × E tests were utilized. Sex-stratified analyses were additionally performed.

Results: Discovery analysis revealed two common intronic variants-rs13118183 (CCDC3) and rs281851 (MARCHF1)-and three rare variant gene sets mapped to SCUBE2, TMEM26, and CPS4FL-to exhibit interaction with EDS. Meta-analysis revealed EDS interaction with 11 rare variant gene sets mapped to UBLCP1, MED31, RAP1GAP, CPNE5, MYMX, YY1, ZNF773, YBEY, IQCB1, PI4K2B, and CORO1A.

Conclusion: Genetic loci reveal connections to cardiovascular risk, insulin resistance, thiamine deficiency, and resveratrol mechanism. Discovered genetic signals may offer insight into pertinent biological pathways for sleep apnea patients with an excessively sleepy subtype. Statement of Significance Sleep apnea is a complex sleep disorder. Exemplifying this is the disparately varying estimates of presence of excessive daytime sleepiness (EDS) in patients, and persistent EDS that lingers despite treatment. Some data indicate that the excessively sleepy subtype of sleep apnea carries heightened cardiovascular risk. Whether EDS influences genetic risk factors underlying sleep apnea has not yet been investigated. This study addresses this gap, as the first genome-wide gene × EDS interaction study for apnea hypopnea index, the standard sleep apnea severity metric. Genetic loci that have been previously unconsidered for sleep apnea are revealed. Discovered interaction signals highlight pathways in metabolism, genes associated with cardiometabolic traits, and therapeutic agents influencing obesity, blood pressure, oxidative stress, and apnea hypopnea index.

Keywords: apnea hypopnea index; excessive daytime sleepiness; gene–environment interaction; sleep apnea.

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Figures

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

**Figure 2**
Common variant × EDS interaction effect on AHI. (a) Manhattan plot of 1df G×E interaction effect displays two common genetic variants 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. 2023;20(8):560–573. 10.1038/s41569-023-00846-6 - DOI - PubMed
1. Szily M, Tarnoki AD, Tarnoki DL, et al. Genetic influences on the onset of obstructive sleep apnoea and daytime sleepiness: a twin study. Respir Res. 2019;20(1):125. 10.1186/s12931-019-1095-x - DOI - PMC - PubMed
1. Sofer T, Kurniansyah N, Murray M, et al. Genome-wide association study of obstructive sleep apnoea in the Million Veteran Program uncovers genetic heterogeneity by sex. EBioMedicine. 2023;90:104536. 10.1016/j.ebiom.2023.104536 - DOI - PMC - PubMed
1. Rosenberg R, Schweitzer PK, Steier J, Pepin JL. Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management. Postgrad Med. 2021;133(7):772–783. 10.1080/00325481.2021.1948305 - DOI - PubMed
1. Huang T, Goodman M, Li X, et al. C-reactive protein and risk of OSA in four US cohorts. Chest. 2021;159(6):2439–2448. 10.1016/j.chest.2021.01.060 - DOI - PMC - PubMed

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Genome-wide gene by sleepiness interaction analysis for sleep apnea

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Genome-wide gene by sleepiness interaction analysis for sleep apnea

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