Year: 2025
Type: article
Study design: Observational Study
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.
Source: SLEEP
Authors: Pavithra Nagarajan, Nuzulul Kurniansyah, Jiwon Lee, Sina A Gharib, Yushan Xu, Yiyan Zhang, Brian Spitzer, Tariq Faquih, Hufeng Zhou, Eric Boerwinkle, Han Chen, Daniel J Gottlieb, Xiuqing Guo, Nancy L Heard-Costa, Bertha A Hidalgo, Daniel Levy, Peter Y Liu, Hao Mei, Rebecca Montalvan, Sutapa Mukherjee, Kari E North, George T O’Connor, Lyle J Palmer, Sanjay R Patel, Bruce M Psaty, Shaun M Purcell, Laura M Raffield, Stephen S Rich, Jerome I Rotter, Richa Saxena, Albert V Smith, Katie L Stone, Xiaofeng Zhu, 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, Brian E Cade, Tamar Sofer, Susan Redline, Heming Wang
Institutions: Brigham and Women's Hospital, University of Washington, Harvard University, Baylor College of Medicine, The University of Texas Health Science Center at Houston, VA Boston Healthcare System, The Lundquist Institute, Harbor–UCLA Medical Center, Boston University, National Heart, Lung, and Blood Institute, Framingham Heart Study, University of Alabama at Birmingham, National Institutes of Health, National Heart, Lung, and Blood Institute Division of Intramural Research, University of Mississippi Medical Center, Westat (United States), Flinders University, SA Health, Adelaide Institute for Sleep Health, University of North Carolina at Chapel Hill, The University of Adelaide, University of Pittsburgh, University of Virginia, Massachusetts General Hospital, University of Michigan, University of California, San Francisco, California Pacific Medical Center, Case Western Reserve University, Beth Israel Deaconess Medical Center
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,388
Funders: U.S. Department of Health and Human Services, University of Miami, University of North Carolina, Jackson State University, San Diego State University, Ontario Institute for Cancer Research, Mississippi State Department of Health, National Institutes of Health, Albert Einstein College of Medicine, Yeshiva University, University of Illinois at Chicago, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Eye Institute, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities
Awards: G1023702118, G125972088, G1261314546, MESA, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, Leveraging Family Data to Identify Genetic Variants for Sleep Apnea, Outcomes of Sleep Disorders in Older Men-Minneapolis, Osteoporotic Fractures in Men (MrOS) - Minneapolis, Hispanic Community Health Study, ASSOCIATION OF SLEEP DISORDERS WITH CARDIOVASCULAR HEALTH ACROSS ETHNIC GROUPS, CORONARY HEART DISEASE AND STROKE, Wake Forest Clinical and Translational Science Award, G1888983140, Case Western Reserve University/Cleveland Clinic CTSA (KL2), Genomic Architecture of Common Disease in Diverse Populations, Large Scale Sequencing and Analysis of Genomes, Oregon Clinical and Translational Research Institute, Genome-wide case-only study of antihypertensive drug-gene interactions, Osteoporatic Fractures in Men (MrOS), Outcomes of Sleep Disorders in Older Men- Reading Center, G215000922, Rare variants and NHLBI traits in deeply phenotyped cohorts, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G232264632, MESA, Institute for Clinical and Translational Research (UL1), HISPANIC COMMUNITY HEALTH STUDY - FIELD CENTER, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G265762973, G270907595, Bone Strength Phenotypes in men: Genes and Environment, G278200998, G2800149121, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, G308844681, Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium, G3220743633, Phenotypic and Molecular Signatures for Sleep Apnea and Related Morbidities, G3256118428, Familial Aggregation and Natural History of Sleep Apnea, Hispanic Community Health Study, G34347772, G3459893998, CHS research resources for the cardiovascular health of older adults, Osteoporotic Fractures in Men (Mr. Os) Palo Alto, GWAS in MrOS and SOF, GWA for Gene-Environment Interaction Effects Influencing CHD, G373996396, MESA, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Rare variants and NHLBI traits in deeply phenotyped cohorts, G423252844, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), G432753757, Hispanic Community Health Study, Osteoporotic Fractures in Men (MrOS) - Administrative Center, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, G4897018079, MESA, G4976486911, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G5223154479, HISPANIC COMMUNITY HEALTH STUDY - COORDINATING CENTER, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G5479317095, G5805320778, CHARGE consortium: omics discovery for CVD and aging phenotypes, G596642789, CHS Events Follow-up Study, Outcomes of Sleep Disorders in Older Men-Portland, Institute for Clinical and Translational Research, The Framingham Heart Study, MESA, Osteoporotic Fractures in Men (Mr.OS), CHS-Transition Phase, Osteoporotic Fractures in Men (MrOS) - San Francisco Coordinating Center, G6902273418, Osteoporotic Fractures in Men (MrOS) - Portland, Outcomes of Sleep Disorders in Older Men-Palo Alto, MESA, Outcomes of Sleep Disorders in Older Men, Osteoporotic Fractures in Men_MrOS Renewal_Birmingham, Outcomes of Sleep Disorders in Older Men, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), Outcomes of Sleep Disorders in Older Men-Birmingham, Clinical and Translational Science Award, Outcomes of Sleep Disorders in Older Men - Pittsburgh, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, Pathway-level transcriptional causal mechanism of sleep disordered breathing, NHGRI Genome Sequencing Program Coordinating Center, G9000127501, Clinical and Translational Science Collaborative of Northern Ohio, Catalyzing Linkages for Everyone's Health (CLE Health), IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVAL, Infrastructure for mentored access to CHS data and specimens, Dissecting heterogeneity of excessive daytime sleepiness and impact on cardiovascular diseases, From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, UCLA Clinical and Translational Science Institute, G905887895
OpenAlex ID: W4412785718