Genome-wide Gene by Sleepiness Interaction Analysis for Sleep Apnea

doi:10.1093/sleep/zsaf212

. 2025 Jul 28:zsaf212.

doi: 10.1093/sleep/zsaf212. Online ahead of print.

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'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 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, USA.
² Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
³ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Department of Biostatistics, 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, USA.
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, USA.
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 Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA.
²⁷ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁸ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁹ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁰ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³¹ California Pacific Medical Center Research Institute, San Francisco and Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.
³² Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
³³ CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.

PMID: 40736211
DOI: 10.1093/sleep/zsaf212

Genome-wide Gene by Sleepiness Interaction Analysis for Sleep Apnea

Pavithra Nagarajan et al. Sleep. 2025.

. 2025 Jul 28:zsaf212.

doi: 10.1093/sleep/zsaf212. Online ahead of print.

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, USA.
² Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
³ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Department of Biostatistics, 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, USA.
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, USA.
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 Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA.
²⁷ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁸ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁹ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³⁰ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³¹ California Pacific Medical Center Research Institute, San Francisco and Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.
³² Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
³³ CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.

PMID: 40736211
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 (AHI), 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 (TOPMed) (N=11619) data, followed by replication and subsequent meta-analysis in additional TOPMed-imputed data (N=8904). The 1 degree-of-freedom (1df) GxE test and the 2df joint G, GxE 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.

Keywords: Apnea-Hypopnea Index; Excessive Daytime Sleepiness; Gene-environment Interaction; Sleep Apnea.

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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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