. 2025 Jul:117:105790.

doi: 10.1016/j.ebiom.2025.105790. Epub 2025 Jun 4.

Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease

Nuzulul Kurniansyah¹, Satu J Strausz², Geetha Chittoor³, Shreyash Gupta³, Anne E Justice³, Yana Hrytsenko⁴, Brendan T Keenan⁵, Brian E Cade⁶, Brian W Spitzer⁷, Heming Wang⁶, Jennifer Huffman⁸, Matthew R Moll⁹, Bernhard Haring¹⁰, Su Yon Jung¹¹, Laura M Raffield¹², Robert Kaplan¹³, Jerome I Rotter¹⁴, Stephen S Rich¹⁵, Sina A Gharib¹⁶, Traci M Bartz¹⁷, Peter Y Liu¹⁸, Han Chen¹⁹, Myriam Fornage²⁰, Lifang Hou²¹, Daniel Levy²², Alanna C Morrison¹⁹, Heather M Ochs-Balcom²³, Bruce M Psaty²⁴, Peter W F Wilson²⁵, Kelly Cho²⁶, Allan I Pack²⁷, Hanna M Ollila²⁸, Susan Redline⁶, Daniel J Gottlieb²⁹, Tamar Sofer³⁰; FinnGen; Trans-Omics in Precision Medicine Consortium; VA Million Veteran Program

Affiliations

¹ VA Boston Healthcare System, Boston, MA, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Bioinformatics, Boston University, Boston, MA, USA.
² Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland; Department of Cleft Palate and Craniofacial Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Orthodontics, Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³ Department of Population Health Sciences, Geisinger Health System, Danville, PA, USA.
⁴ Department of Medicine, Harvard Medical School, Boston, MA, USA; CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁵ Division of Sleep Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁷ CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA; Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, MA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
⁹ Department of Medicine, Harvard Medical School, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Section on Pulmonary, Critical Care, Sleep, and Allergy, Veterans Affairs Boston Healthcare System, West Roxbury, MA, USA.
¹⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine III, Saarland University, Homburg, Germany.
¹¹ Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA; Translational Sciences Section, School of Nursing, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
¹² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁵ Department of Genome Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Division of Pulmonary, Critical Care and Sleep Medicine, Computational Medicine Core, Center for Lung Biology, University of Washington, Seattle, WA, USA.
¹⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁸ Division of Genetics, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁹ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁰ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
²¹ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
²² The Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, MD, USA; The Framingham Heart Study, Framingham, MA, USA.
²³ Department of Epidemiology and Environmental Health, University of Buffalo, Buffalo, NY, USA.
²⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Health Systems and Population Health, University of Washington, Seattle, WA, USA.
²⁵ Atlanta VA Healthcare System, Decatur, GA, USA; Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
²⁶ VA Boston Healthcare System, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Aging, Brigham and Women's Hospital, Department of Medicine, Boston, MA, USA.
²⁷ Circadian Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
²⁹ VA Boston Healthcare System, Boston, MA, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁰ VA Boston Healthcare System, Boston, MA, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: tsofer@bidmc.harvard.edu.

PMID: 40472801
PMCID: PMC12171572
DOI: 10.1016/j.ebiom.2025.105790

Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease

Nuzulul Kurniansyah et al. EBioMedicine. 2025 Jul.

. 2025 Jul:117:105790.

doi: 10.1016/j.ebiom.2025.105790. Epub 2025 Jun 4.

Authors

Affiliations

¹ VA Boston Healthcare System, Boston, MA, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Bioinformatics, Boston University, Boston, MA, USA.
² Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland; Department of Cleft Palate and Craniofacial Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Orthodontics, Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³ Department of Population Health Sciences, Geisinger Health System, Danville, PA, USA.
⁴ Department of Medicine, Harvard Medical School, Boston, MA, USA; CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁵ Division of Sleep Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁷ CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA; Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, MA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
⁹ Department of Medicine, Harvard Medical School, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Section on Pulmonary, Critical Care, Sleep, and Allergy, Veterans Affairs Boston Healthcare System, West Roxbury, MA, USA.
¹⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine III, Saarland University, Homburg, Germany.
¹¹ Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA; Translational Sciences Section, School of Nursing, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
¹² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁵ Department of Genome Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Division of Pulmonary, Critical Care and Sleep Medicine, Computational Medicine Core, Center for Lung Biology, University of Washington, Seattle, WA, USA.
¹⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁸ Division of Genetics, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁹ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁰ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
²¹ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
²² The Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, MD, USA; The Framingham Heart Study, Framingham, MA, USA.
²³ Department of Epidemiology and Environmental Health, University of Buffalo, Buffalo, NY, USA.
²⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Health Systems and Population Health, University of Washington, Seattle, WA, USA.
²⁵ Atlanta VA Healthcare System, Decatur, GA, USA; Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
²⁶ VA Boston Healthcare System, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Aging, Brigham and Women's Hospital, Department of Medicine, Boston, MA, USA.
²⁷ Circadian Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
²⁹ VA Boston Healthcare System, Boston, MA, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁰ VA Boston Healthcare System, Boston, MA, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: tsofer@bidmc.harvard.edu.

PMID: 40472801
PMCID: PMC12171572
DOI: 10.1016/j.ebiom.2025.105790

Abstract

Background: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors.

Methods: Using race/ethnic diverse samples from over 1.2 million individuals from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger's MyCode, MGB Biobank, and the Human Phenotype Project, we developed and assessed PGSs for OSA, both without (BMIunadjOSA-PGS) and with adjustment for the genetic contributions of BMI (BMIadjOSA-PGS).

Findings: Adjusted odds ratios (ORs) for OSA per 1 standard deviation of the PGSs ranged from 1.38 to 2.75. The associations of BMIadjOSA- and BMIunadjOSA-PGSs with CVD outcomes in AoU shared both common and distinct patterns. Only BMIunadjOSA-PGS was associated with type 2 diabetes, heart failure, and coronary artery disease, while both BMIadjOSA- and BMIunadjOSA-PGSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA-PGS association with hypertension was driven by females (OR = 1.1, p-value = 0.002, OR = 1.01 p-value = 0.2 in males). OSA PGSs were also associated with body fat measures with some sex-specific associations.

Interpretation: Distinct components of OSA genetic risk are related and independent of obesity. Sex-specific associations with body fat distribution measures may explain differing OSA risks and associations with cardiometabolic morbidities between sexes.

Funding: R01AG080598.

Keywords: Body fat distribution; Diverse populations; Genetically determined OSA; Sex differences.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests Dr. Cade reports receiving grants from the National Institute of Health (NIH) and from the American Academy of Sleep Medicine Foundation, and an unpaid consultancy, with a paid consulting agreement in progress through the institution, to Apnimed. Dr. Chen reports receiving consulting fees from Character Biosciences. Dr. Gottlieb reports receiving personal consulting fees from Powell Mansfield, Inc., Lilly USA, LLC, and Takeda Development Center Americas, Inc. He also reports receiving lecture honoraria from SleepRes, Inc, and from ProSomnus Sleep Technologies, and participation on a Data Safety Monitoring Board or Advisory Board for SleepRes, Inc and ProSomnus Sleep Technologies. Dr. Gupta held investment stocks of Eli Lilly (purchased in February 2024 and sold in January 2025) and of Regeneron (purchased in October 2024). Dr. Haring reports receiving lecture fees from Bristol Myers Squibb, Inari. Boehringer Ingelheim, and Pfizer, unrelated to the content of this manuscript. Dr. Keenan reports receiving support from grant P01HL160471 (Developing a P4 Medicine Approach to Obstructive Sleep Apnoea). Dr. Levy reports receiving honoraria for journal editing, as the editor in chief for IJC Cardiovascular Risk and Prevention. Dr. Moll reports receiving NIH grant K08HL159318, and a Genentech sponsored research agreement, with payments made to the institution. He also reports receiving consulting fees from 2ndMD, TheaHealth, Axon Advisors, Dialectica, Sanofi, and Verona Pharma, with payments made to him. Dr. Moll further reports payments or honoraria and travel support for lectures at the ATS 2024 and NYSTS 2024 conferences, with payments made to him. Dr. Psaty reports receiving NIH grant support, as reported in the CHS study acknowledgements, participation in the Steering Committee of the Yale Open Data Access Project, funded by Johnson & Johnson, and serving as a chair of the Board of Directors of the Am J Hypertension. Dr. Raffield reports receiving consulting fees as a consultant to the TOPMed Administrative Coordinating Center via Westat®. Dr. Redline reports receiving consulting fees from Eli Lilly, related to work on GLP-1 and OSA, with payments made to her. Dr. Rich reports receiving consulting fees from Westat, as a consultant to the Administrative Coordinating Center for the NHLBI Trans-Omics for Precision Medicine program. Dr. Rotter reports NIH grant support. Dr. Sofer reports grant support from the National Institute on Aging and from the National Heart Lung and Blood Institute, with payments made to the institution.

Figures

**Fig. 1**
**OSA PGS development and assessment**. Development and assessment of OSA PGSs. The steps are composed of (a) PGS training using GWAS summary statistics, reference panels, and a separate population for computing PGS summation weights; (b) evaluation step used to select PGS out of multiple candidates; (c) validation of associations with OSA in new independent datasets; and (d) follow up analyses addressing OSA PGS associations with OSA within various strata, associations with related sleep phenotypes, comorbidities, and sequelae of OSA. Analyses in step (d) were in datasets from previous steps. OSA, obstructive sleep apnoea; PGS, polygenic score; GWAS, genome-wide association study.

**Fig. 2**
**OSA PGS associations with OSA in TOPMed individuals**. Panel a: distributions of BMIadjOSA- and BMIunadjOSA-PGSs in strata defined by self-reported race/ethnicity. Panel b: percentages and numbers of individuals with normal, mild, moderate, and severe OSA (defined by cut-points of REI/AHI of 5, 15, and 30), in quintiles of the OSA PGSs by self-reported race/ethnicity (Asian group excluded due to low sample size). Limited to individuals with measured REI/AHI. Panel c: estimated OSA PGS associations with OSA in TOPMed combined and stratified samples. Analyses were adjusted for age, sex (unless sex-stratified), self-reported race/ethnicity (unless stratified by that), and BMI (both linear and squared terms). AHI, apnoea-hypopnea index; OSA, obstructive sleep apnoea; PGS, polygenic score; REI, respiratory event index.

**Fig. 3**
**Estimated associations of OSA PGSs with OSA- and sleep-related phenotypes in TOPMed**. Results from association analyses of OSA PGSs with OSA-related sleep measures. Panel a: measures that tend to be higher with more severe OSA, panel b: measures that tend to be lower with more severe OSA. AHI, apnoea-hypopnea index; NREM, non-rapid eye movement sleep; REI, respiratory event index; REM, rapid eye movement sleep; Avg SatO2, average oxyhaemoglobin saturation during sleep; Min SatO2, minimum oxyhaemoglobin saturation during sleep; Avg DesatO2, average oxyhaemoglobin desaturation during respiratory events.

**Fig. 4**
**OSA PGS associations with OSA in validation studies**. Estimated associations of BMIadjOSA- and BMIunadjOSA-PGSs with OSA in three validation datasets: All of Us, Geinsinger health system's MyCode, and the Human Phenotype Project, in combined and stratified analyses. BMI, body mass index; OSA, obstructive sleep apnoea; PGS, polygenic score.

**Fig. 5**
**OSA PGS associations with quantitative OSA phenotypes in the Human Phenotype Project**. Estimated associations of BMIadjOSA-PGS and BMIunadjOSA-PGS with sleep monitoring, log-transformed OSA-related measures in the HPP, stratified by REM and NREM sleep and combined. All measures were averaged over the three nights of sleep monitoring. AHI, peripheral arterial tonometry-derived apnoea-hypopnea index; HPP, Human Phenotype Project; ODI, oxygen desaturation index; RDI, respiratory disturbance index; REM, rapid eye movement; NREM, non-REM.

**Fig. 6**
**OSA PGS associations with other clinical outcomes in All of Us**. Estimated associations of BMIadjOSA and BMIunadjOSA PGSs with clinical outcomes in the All of Us study. Associations were adjusted for age, sex, BMI (linear and squared terms), and 10 PCs of genetic ancestry. BMI, body mass index; COPD, chronic obstructive pulmonary disease; OSA, obstructive sleep apnoea; PGS, polygenic score; PC, principal component.

**Fig. 7**
**Sex-stratified associations OSA PGSs with cardiometabolic traits and body fat distribution measures from DXA scan**. Panel a: Estimated adjusted odds ratio of OSA PGSs with hypertension and T2D in All of Us. Panels b and c: estimated associations of BMIadjOSA-PGS with DXA measures in HPP. All associations were adjusted for age, sex, BMI (linear and squared terms), and the 10 first genetic principal components. Results from association analyses that used BMIunadjOSA-PGS and was not adjusted for BMI are provided in Supplementary Figure S18. BMI, body mass index; DXA, dual-energy X-ray absorptiometry; HPP, human phenotype project; OSA, obstructive sleep apnoea; PGS, polygenic score; OR, odds ratio; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; FM, fat mass; TFM, total scan fat mass; T2D, type 2 diabetes.

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Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease

Affiliations

Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources