Evidence map›Paper›PMID 40736211›Full record

ArticleSleep2026

Genome-wide gene by sleepiness interaction analysis for sleep apnea.

Pavithra Nagarajan, Nuzulul Kurniansyah, Jiwon Lee, Sina A Gharib, Yushan Xu, Yiyan Zhang, Brian Spitzer, Tariq Faquih, Hufeng Zhou, Eric Boerwinkle and 28 more

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In one paragraph

Article in Sleep, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. The promise and peril of data-driven approaches: interpreting the association of insomnia, sleep apnea, and COMISA with mortality in US veterans.Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine · 2026
    Article
  2. Article
4 · The record

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5 · Who and what money

Authors and funding

38 authors.

Pavithra NagarajanDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.ORCID 0000-0002-0036-9970
Nuzulul KurniansyahDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Jiwon LeeDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Sina A GharibDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States.ORCID 0000-0002-2480-4367
Yushan XuDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Yiyan ZhangDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Brian SpitzerDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Tariq FaquihDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.ORCID 0000-0001-8026-2251
Hufeng ZhouDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Han ChenHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States.ORCID 0000-0002-9510-4923
Daniel J GottliebDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.ORCID 0000-0001-8812-8751
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States.ORCID 0000-0002-5264-5068
Nancy L Heard-CostaDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States.
Bertha A HidalgoDepartment of Epidemiology, School of Public Health, University of Alabama at Birmingham School of Public Health, Birmingham, AL, United States.
Daniel LevyNational Heart, Lung, and Blood Institute and Boston University's, Framingham Heart Study, Framingham, MA, United States.
Peter Y LiuThe Institute for Translational Genomics and Population Sciences, Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States.ORCID 0000-0003-2439-0915
Hao MeiDepartment of Data Science, University of Mississippi Medical Center, Jackson, MS, United States.
Rebecca MontalvanWestat Inc., Rockville, MD, United States.
Sutapa MukherjeeAdelaide Institute for Sleep Health/Flinders University College of Medicine and Public Health, Bedford Park, SA, Australia.
Kari E NorthDepartment of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
George T O'ConnorNational Heart, Lung, and Blood Institute and Boston University's, Framingham Heart Study, Framingham, MA, United States.
Lyle J PalmerAustralian Institute for Machine Learning, University of Adelaide, Adelaide, SA, Australia.
Sanjay R PatelCenter for Sleep and Cardiovascular Outcomes Research, University of Pittsburgh, Pittsburgh, PA, United States.ORCID 0000-0002-9142-5172
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States.
Shaun M PurcellDivision of Sleep Medicine, Harvard Medical School, Boston, MA, United States.ORCID 0000-0002-7402-5812
Laura M RaffieldDepartment of Genetics, University of North Carolina, Chapel Hill, NC, United States.ORCID 0000-0002-7892-193X
Stephen S RichDepartment of Genome Sciences, University of Virginia, Charlottesville, VA, United States.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States.
Richa SaxenaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States.
Albert V SmithDepartment of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, United States.
Katie L StoneCalifornia Pacific Medical Center Research Institute, San Francisco and Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States.
Xiaofeng ZhuDepartment of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, United States.
TOPMed Sleep Trait Working Group
Brian E CadeDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.ORCID 0000-0003-1424-0673
Tamar SoferDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.ORCID 0000-0001-8520-8860
Susan RedlineDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.ORCID 0000-0002-6585-1610
Heming WangDivision of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.ORCID 0000-0002-1486-7495

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Genomic Architecture of Common Disease in Diverse Populations: WGS of Ongoing Hemorrhagic Stroke Study SupplementUM1HG008898 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2016 to 2020
$77.0M
Institute for Clinical and Translational Research (UL1)UL1RR025005 · NCRR · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2007 to 2011
$75.8M
Institute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1M
Wake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3M
Clinical and Translational Science Collaborative of Northern Ohio, Catalyzing Linkages to Equity in Health (CLE Health)UM1TR004528 · NCATS · CASE WESTERN RESERVE UNIVERSITY · PI GRACE A MCCOMSEY · 2023 to 2026
$32.1M
FRAMINGHAM HEART STUDY - YEAR 5 EXAM75N92019D00031 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · PI RAMACHANDRAN, VASAN · 2019 to 2024
$29.8M
Oregon Clinical and Translational Research InstituteUL1TR000128 · NCATS · OREGON HEALTH & SCIENCE UNIVERSITY · PI ELLISON, DAVID H · 2012 to 2015
$28.7M
Clinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2M
Genome-Wide Association Analysis in Essential Hypertension (FEHGAS study)R01HL086694 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ARAVINDA CHAKRAVARTI · 2007 to 2026
$21.2M
IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6M
Albert Einstein College of Medicine HHSN268201300002I/N01-HC-65235Baylor College of Medicine Human Genome Sequencing Center 3U54HG003273-12S2/HHSN268201500015CBaylor College of Medicine Human Genome Sequencing Center HHSN268201600033IBaylor College of Medicine Human Genome Sequencing Center and Broad Institute of MIT and Harvard 3R01HL092577-06S1Baylor College of Medicine Human Genome Sequencing Center and Broad Institute of MIT and Harvard 3U54HG003273-12S2/HHSN268201500015CCentre for Genetic Epidemiology and Biostatistics at the University of Western AustraliaMcLaughlin Centre Accelerator Grant from the University of TorontoMESA 75N92025D00022MESA 75N92025D00024MESA 75N92025D00025MESA 75N92025D00026MESA 75N92025D00027MESA 75N92025D00028MESA N01-HC-95159MESA N01-HC-95160MESA N01-HC-95161MESA N01-HC-95162MESA N01-HC-95163MESA N01-HC-95164MESA N01-HC-95165MESA N01-HC-95166MESA N01-HC-95167MESA N01-HC-95168MESA N01-HC-95169MESA R01HL105756MESA UL1-TR-000040MESA UL1-TR-001079MESA UL1-TR-001420MESA UL1TR001881National Institutes of Health and NIH Roadmap for Medical Research UL1RR025005NCATSNCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR000128NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NCATS NIH HHS UM1 TR004528NCRR NIH HHS KL2 RR024990NCRR NIH HHS UL1 RR025005NEI NIH HHSNHGRINHGRI NIH HHS R01HL086694NHGRI NIH HHS R01HL087641NHGRI NIH HHS U01 HG004402NHGRI NIH HHS U01HG004402NHGRI NIH HHS U24 HG008956NHGRI NIH HHS U54 HG003067NHGRI NIH HHS UM1 HG008898NHLBINHLBI NIH HHS 75N92019D00031NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS 75N92021D00006NHLBI NIH HHS 75N92022D00001NHLBI NIH HHS 75N92022D00002NHLBI NIH HHS 75N92022D00003NHLBI NIH HHS 75N92022D00004NHLBI NIH HHS 75N92022D00005NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201100037CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201300005CNHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS HHSN268201500015CNHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS HHSN268201800010INHLBI NIH HHS HHSN268201800011CNHLBI NIH HHS HHSN268201800011INHLBI NIH HHS HHSN268201800012CNHLBI NIH HHS HHSN268201800012INHLBI NIH HHS HHSN268201800014CNHLBI NIH HHS HHSN268201800014INHLBI NIH HHS HHSN268201800015INHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC065233NHLBI NIH HHS N01 HC065234NHLBI NIH HHS N01 HC065235NHLBI NIH HHS N01 HC065236NHLBI NIH HHS N01 HC065237NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS N01HC55222NHLBI NIH HHS N01HC85079NHLBI NIH HHS N01HC85080NHLBI NIH HHS N01HC85081NHLBI NIH HHS N01HC85082NHLBI NIH HHS N01HC85083NHLBI NIH HHS N01HC85086NHLBI NIH HHS NO1-HC-25195NHLBI NIH HHS R01 HL046380NHLBI NIH HHS R01 HL070837NHLBI NIH HHS R01 HL070838NHLBI NIH HHS R01 HL070839NHLBI NIH HHS R01 HL070841NHLBI NIH HHS R01 HL070842NHLBI NIH HHS R01 HL070847NHLBI NIH HHS R01 HL070848NHLBI NIH HHS R01 HL071194NHLBI NIH HHS R01 HL085251NHLBI NIH HHS R01HL085251NHLBI NIH HHS R01 HL086694NHLBI NIH HHS R01 HL087641NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01HL087652NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL092577-06S1NHLBI NIH HHS R01 HL098433NHLBI NIH HHS R01 HL103612NHLBI NIH HHS R01HL103612NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01HL105756NHLBI NIH HHS R01 HL113338NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01HL120393NHLBI NIH HHS R01 HL153814NHLBI NIH HHS R01HL153814NHLBI NIH HHS R01 HL172803NHLBI NIH HHS R01HL1772803NHLBI NIH HHS R21 HL165324NHLBI NIH HHS R35 HL135818NHLBI NIH HHS R35HL135818NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01HL080295NHLBI NIH HHS U01 HL120393NHLBI NIH HHS U01 HL130114NHLBI NIH HHS U01HL130114NHLBI TOPMed: Genomic Activities such as Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study phs000974NHLBI TOPMed-NHGRI CCDG: Atherosclerosis Risk in Communities (ARIC) phs001211NHLBI TOPMed-NHGRI CCDG: Hispanic Community Health Study/Study of Latinos (HCHS/SOL) phs001395NHLBI TOPMed: NHLBI TOPMed: MESA phs001416NHLBI TOPMed: The Cleveland Family Study (CFS) phs000954NHLBI TOPMed: The Jackson Heart Study phs000964NHLBI TOPMed: Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Project: Cardiovascular Health Study phs001368NIANIAMS NIH HHS R01 AR051124NIAMS NIH HHS RC2 AR058973NIAMS NIH HHS U01 AR066160NIA NIH HHS R01 AG023629NIA NIH HHS R01AG023629NIA NIH HHS U01 AG027810NIA NIH HHS U01 AG042124NIA NIH HHS U01 AG042139NIA NIH HHS U01 AG042140NIA NIH HHS U01 AG042143NIA NIH HHS U01 AG042145NIA NIH HHS U01 AG042168NIDCR NIH HHS HHSN268201300005C AM03NIDCR NIH HHS MOD03NIEHS NIH HHS HHSN268201600033CNIHNIH HHS 75N98025D00022NIH HHS 75N98025D00024NIH HHS 75N98025D00025NIH HHS 75N98025D00026NIH HHS 75N98025D00027NIH HHS 75N98025D00028NIH HHS HHSN268200625226CNIH HHS KL2-RR024990NIH HHS R01-HL046380NIH HHS R01-HL113338NIH HHS R35-HL135818NIMHD NIH HHS HHSN268201800013ININDS NIH HHSOntario Institute for Cancer ResearchSan Diego State University HHSN268201300005I/N01-HC-65237Sir Charles Gairdner and Hollywood Private Hospital Research FoundationsTOPMed Data Coordinating Center HHSN268201800001ITOPMed Data Coordinating Center R01HL-120393TOPMed Data Coordinating Center U01HL-120393TOPMed Informatics Research Center 3R01HL-117626-02S1TOPMed Informatics Research Center HHSN268201800002IUniversity of Illinois at Chicago HHSN268201300003I/N01-HC-65236University of Miami HHSN268201300004I/N01-HC-65234University of North Carolina HHSN268201300001I/N01-HC-65233University of Washington Northwest Genomics Center 3R01HL098433-05S1U.S. Department of Health and Human ServicesWestern Australian Sleep Disorders Research InstituteWestern Australian Sleep Health Study
6 · The paper itself

Abstract

STUDY

objectivesExcessive 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.

methodsDiscovery 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.

resultsDiscovery 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.

conclusionGenetic 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.

Indexed as

Disorders of Excessive SomnolenceGenome-Wide Association StudySleep Apnea SyndromesAdultFemaleGenetic Predisposition to DiseaseHumansMaleMembrane ProteinsMiddle AgedPolymorphism, Single NucleotideMembrane Proteinsapnea hypopnea indexexcessive daytime sleepinessgene–environment interactionsleep apnea

Identifiers

PMID40736211
PMCPMC12795742

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