Genome-wide gene by sleepiness interaction analysis for sleep apnea

TOPMed Sleep Trait Working Group

doi:10.1093/sleep/zsaf212

Genome-wide gene by sleepiness interaction analysis for sleep apnea

TOPMed Sleep Trait Working Group

University at Buffalo, Stony Brook University

Brigham and Women’s Hospital
University of Washington
Harvard University
University of Texas Health Science Center at Houston
Baylor College of Medicine
Department of Veterans Affairs
University of California at Los Angeles
Boston University
Framingham Heart Study
University of Alabama at Birmingham
National Institutes of Health
University of Mississippi
Westat
Flinders University
SA Health
University of North Carolina at Chapel Hill
Adelaide University
University of Pittsburgh
University of Virginia
Massachusetts General Hospital
University of Michigan, Ann Arbor
University of California at San Francisco
Case Western Reserve University
Beth Israel Deaconess Medical Center
University of Washington
Harvard University
Boston University
The National Heart Lung and Blood Institute's Framingham Heart Study
University of Michigan, Ann Arbor

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	zsaf212
Journal	Sleep
Volume	49
Issue number	1
DOIs	https://doi.org/10.1093/sleep/zsaf212
State	Published - Jan 1 2026

Keywords

apnea hypopnea index
excessive daytime sleepiness
gene-environment interaction
sleep apnea

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10.1093/sleep/zsaf212

Cite this

@article{eb03de10c17c4c4f811ca6fd19f9227b,

title = "Genome-wide gene by sleepiness interaction analysis for sleep apnea",

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",

author = "\{TOPMed Sleep Trait Working Group\} and Pavithra Nagarajan and Nuzulul Kurniansyah and Jiwon Lee and Gharib, \{Sina A.\} and Yushan Xu and Yiyan Zhang and Brian Spitzer and Tariq Faquih and Hufeng Zhou and Eric Boerwinkle and Han Chen and Gottlieb, \{Daniel J.\} and Xiuqing Guo and Heard-Costa, \{Nancy L.\} and Hidalgo, \{Bertha A.\} and Daniel Levy and Liu, \{Peter Y.\} and Hao Mei and Rebecca Montalvan and Sutapa Mukherjee and North, \{Kari E.\} and O'Connor, \{George T.\} and Palmer, \{Lyle J.\} and Patel, \{Sanjay R.\} and Psaty, \{Bruce M.\} and Purcell, \{Shaun M.\} and Raffield, \{Laura M.\} and Rich, \{Stephen S.\} and Rotter, \{Jerome I.\} and Richa Saxena and Smith, \{Albert V.\} and Stone, \{Katie L.\} and Xiaofeng Zhu and Cade, \{Brian E.\} and Tamar Sofer and Susan Redline and Heming Wang and Trevor Bierig and Brian Cade and Geetha Chittoor and Danielle Clarkson-Townsend and Daniel Cohen and Megan Duff and Joyita Dutta and Lynette Ekunwe and Sina Gharib and Matthew Goodman and Daniel Gottlieb and Einat Granot-Hershkovitz and Heather Ochs-Balcom and Lauren Hale",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Published by Oxford University Press on behalf of Sleep Research Society.",

year = "2026",

month = jan,

day = "1",

doi = "10.1093/sleep/zsaf212",

language = "English",

volume = "49",

journal = "Sleep",

issn = "0161-8105",

publisher = "Oxford University Press",

number = "1",

}

TY - JOUR

T1 - Genome-wide gene by sleepiness interaction analysis for sleep apnea

AU - TOPMed Sleep Trait Working Group

AU - Nagarajan, Pavithra

AU - Kurniansyah, Nuzulul

AU - Lee, Jiwon

AU - Gharib, Sina A.

AU - Xu, Yushan

AU - Zhang, Yiyan

AU - Spitzer, Brian

AU - Faquih, Tariq

AU - Zhou, Hufeng

AU - Boerwinkle, Eric

AU - Chen, Han

AU - Gottlieb, Daniel J.

AU - Guo, Xiuqing

AU - Heard-Costa, Nancy L.

AU - Hidalgo, Bertha A.

AU - Levy, Daniel

AU - Liu, Peter Y.

AU - Mei, Hao

AU - Montalvan, Rebecca

AU - Mukherjee, Sutapa

AU - North, Kari E.

AU - O'Connor, George T.

AU - Palmer, Lyle J.

AU - Patel, Sanjay R.

AU - Psaty, Bruce M.

AU - Purcell, Shaun M.

AU - Raffield, Laura M.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Saxena, Richa

AU - Smith, Albert V.

AU - Stone, Katie L.

AU - Zhu, Xiaofeng

AU - Cade, Brian E.

AU - Sofer, Tamar

AU - Redline, Susan

AU - Wang, Heming

AU - Bierig, Trevor

AU - Cade, Brian

AU - Chittoor, Geetha

AU - Clarkson-Townsend, Danielle

AU - Cohen, Daniel

AU - Duff, Megan

AU - Dutta, Joyita

AU - Ekunwe, Lynette

AU - Gharib, Sina

AU - Goodman, Matthew

AU - Gottlieb, Daniel

AU - Granot-Hershkovitz, Einat

AU - Ochs-Balcom, Heather

AU - Hale, Lauren

PY - 2026/1/1

Y1 - 2026/1/1

N2 - 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.

AB - 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.

KW - apnea hypopnea index

KW - excessive daytime sleepiness

KW - gene-environment interaction

KW - sleep apnea

UR - https://www.scopus.com/pages/publications/105027242773

U2 - 10.1093/sleep/zsaf212

DO - 10.1093/sleep/zsaf212

M3 - Article

C2 - 40736211

SN - 0161-8105

VL - 49

JO - Sleep

JF - Sleep

IS - 1

M1 - zsaf212

ER -

Genome-wide gene by sleepiness interaction analysis for sleep apnea

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Keywords

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