A genome-wide cross-trait analysis identifies shared loci and causal relationships of respiratory diseases and obstructive sleep apnea_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LIU Shaoqing ^1,2 , REN Xiaolei ¹ , WANG Yushi ¹ , TAN Zhaoqi ¹ , GAO Ming ^1,3 , CHEN Hai ^1,2 , CHEN Yu ^1,2,4 ,  LI Jiqiang ^1,2 ,  CHEN Jiankun ^1,2

1. The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P. R. China;
2. The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China;
3. Nanhai District Hospital of Chinese Medicine (Guangdong Provincial Hospital of Integrated Chinese and Western Medicine), Foshan, Guangdong, 528000 P. R. China;
4. State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China;

Corresponding?author：

LI Jiqiang, Email: lijiqiangjizhen@163.com; CHEN Jiankun, Email: chenjiankundoctor@126.com

Keywords：

Respiratory diseases; obstructive sleep apnea; genetic correlation; genome-wide cross-trait analysis; Mendelian randomization

DOI：

10.7507/1671-6205.202507012

Video：

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Objective To explore the shared genetic structure and causal relationship between respiratory diseases and obstructive sleep apnea (OSA) through comprehensive genetic analysis. Methods In this study, we utilized large-scale genome-wide association studies (GWAS) summary statistics and novel statistical genetic approaches. We incorporated genetic data related to respiratory diseases to align with OSA. We conducted a genome-wide cross-trait analysis to assess genetic correlation, identify shared loci, examine expression-trait associations, and infer causal relationships. Results We found positive genetic correlation between acute upper respiratory infections and OSA (r_g=0.435, P=3.47×10^?14), acute lower respiratory infections and OSA (r_g=0.481, P=4.03×10^?5), acute bronchitis and OSA (r_g=0.453, P=7.00×10^?4), pneumonia and OSA (r_g=0.368, P=7.94×10^?10), asthma and OSA (r_g=0.364, P=2.73×10^?19), and COPD and OSA (r_g=0.300, P=1.10×10^?10). We conducted a cross-trait meta-analysis to identify shared loci between respiratory diseases and OSA. Additionally, we employed summary-based Mendelian randomization (SMR) to predict causal genes associated with both respiratory diseases and OSA. Mendelian randomization (MR) supported the causal roles of pneumonia (IVW OR=1.15; 95%CI 1.02-1.30), asthma (IVW OR=1.05, 95%CI 1.01-1.08) in OSA, while not observe any significant association between other respiratory diseases and the risk of OSA. Conclusions An intrinsic link between respiratory diseases and OSA has been demonstrated. The genetic correlation and causal role of respiratory diseases in OSA emphasize the importance of considering respiratory health in the management of OSA.

Citation： LIU Shaoqing, REN Xiaolei, WANG Yushi, TAN Zhaoqi, GAO Ming, CHEN Hai, CHEN Yu, LI Jiqiang, CHEN Jiankun. A genome-wide cross-trait analysis identifies shared loci and causal relationships of respiratory diseases and obstructive sleep apnea. Chinese Journal of Respiratory and Critical Care Medicine, 2026, 25(5): 309-318. doi: 10.7507/1671-6205.202507012 Copy

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1. Gottlieb DJ, Punjabi NM. Diagnosis and management of obstructive sleep apnea: a review. JAMA, 2020, 323(14): 1389-1400.
2. Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA, 2004, 291(16): 2013-2016.
3. Jordan AS, Mcsharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet, 2014, 383(9918): 736-747.
4. Akset M, Poppe KG, Kleynen P, et al. Endocrine disorders in obstructive sleep apnoea syndrome: a bidirectional relationship. Clin Endocrinol (Oxf), 2023, 98(1): 3-13.
5. Díaz-García E, García-Tovar S, Alfaro E, et al. Inflammasome activation: a keystone of proinflammatory response in obstructive sleep apnea. Am J Respir Crit Care Med, 2022, 205(11): 1337-1348.
6. Sunwoo BY, Owens RL. Sleep deficiency, sleep apnea, and chronic lung disease. Clin Chest Med, 2022, 43(2): 337-352.
7. Hariyanto TI, Kurniawan A. Obstructive sleep apnea (OSA) and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: a systematic review and meta-analysis. Sleep Med, 2021, 82: 47-53.
8. Maas MB, Kim M, Malkani RG, et al. Obstructive sleep apnea and risk of COVID-19 infection, hospitalization and respiratory failure. Sleep Breath, 2021, 25(2): 1155-1157.
9. Miller MA, Cappuccio FP. A systematic review of COVID-19 and obstructive sleep apnoea. Sleep Med Rev, 2021, 55: 101382.
10. R?gnvaldsson KG, Eytórsson ES, Emilsson ? I, et al. Obstructive sleep apnea is an independent risk factor for severe COVID-19: a population-based study. Sleep, 2022, 45(3): zsab272.
11. Strausz S, Kiiskinen T, Broberg M, et al. Sleep apnoea is a risk factor for severe COVID-19. BMJ Open Respir Res, 2021, 8(1): e000845. doi: 10.1136/bmjresp-2020-000845. P.
12. Chen TY, Chang R, Chiu LT, et al. Obstructive sleep apnea and influenza infection: a nationwide population-based cohort study. Sleep Med, 2021, 81: 202-209.
13. Su VY, Liu CJ, Wang HK, et al. Sleep apnea and risk of pneumonia: a nationwide population-based study. Cmaj, 2014, 186(6): 415-421.
14. Chiner E, Llombart M, Valls J, et al. Association between obstructive sleep apnea and community-acquired pneumonia. PLoS One, 2016, 11(4): e0152749.
15. Ioachimescu OC, Janocko NJ, Ciavatta MM, et al. Obstructive lung disease and obstructive sleep apnea (OLDOSA) cohort study: 10-year assessment. J Clin Sleep Med, 2020, 16(2): 267-277.
16. Tiotiu A, Novakova P, Baiardini I, et al. Manifesto on united airways diseases (UAD): an interasma (global asthma association - GAA) document. J Asthma, 2022, 59(4): 639-654.
17. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med, 2011, 183(6): 788-824.
18. 馬德東, 趙恩琪, 浦英. 特發性肺纖維化與阻塞性睡眠呼吸暫停. 內科理論與實踐, 2021, 16(2): 84-87.
19. Khatri SB, Ioachimescu OC. The intersection of obstructive lung disease and sleep apnea. Cleve Clin J Med, 2016, 83(2): 127-140.
20. Owens RL, Macrea MM, Teodorescu M. The overlaps of asthma or COPD with OSA: a focused review. Respirology, 2017, 22(6): 1073-1083.
21. Puthalapattu S, Ioachimescu OC. Asthma and obstructive sleep apnea: Clinical and pathogenic interactions. J Investig Med, 2014, 62(4): 665-675.
22. Kendzerska T, Leung RS, Aaron SD, et al. Cardiovascular outcomes and all-cause mortality in patients with obstructive sleep apnea and chronic obstructive pulmonary disease (Overlap Syndrome). Ann Am Thorac Soc, 2019, 16(1): 71-81.
23. Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology, 2013, 18(3): 421-431.
24. Grotzinger AD, Mallard TT, Akingbuwa WA, et al. Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. Nat Genet, 2022, 54(5): 548-559.
25. Yang Y, Musco H, Simpson-Yap S, et al. Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases. Nat Commun, 2021, 12(1): 5641.
26. Gao X, Wei T, Wang H, et al. Causal associations between obstructive sleep apnea and COVID-19: a bidirectional mendelian randomization study. Sleep Med, 2023, 101: 28-35.
27. Kurki MI, Karjalainen J, Palta P, et al. Finngen provides genetic insights from a well-phenotyped isolated population. Nature, 2023, 613(7944): 508-518.
28. Strausz S, Ruotsalainen S, Ollila HM, et al. Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health. Eur Respir J, 2021, 57(5): 2003091.
29. Bulik-Sullivan B, Finucane HK, Anttila V, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet, 2015, 47(11): 1236-1241.
30. Zhu X, Feng T, Tayo BO, et al. Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension. Am J Hum Genet, 2015, 96(1): 21-36.
31. Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell, 2019, 179(7): 1469-1482. e1411.
32. Purcell S, Neale B, Todd-Brown K, et al. Plink: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet, 2007, 81(3): 559-575.
33. Zhang L, Zhang W, He L, et al. Impact of gallstone disease on the risk of stroke and coronary artery disease: Evidence from prospective observational studies and genetic analyses. BMC Med, 2023, 21(1): 353.
34. Mclaren W, Gil L, Hunt SE, et al. The Ensembl variant effect predictor. Genome Biol, 2016, 17(1): 122.
35. Liu H, Sun Y, Zhang X, et al. Integrated analysis of summary statistics to identify pleiotropic genes and pathways for the comorbidity of schizophrenia and cardiometabolic disease. Front Psychiatry, 2020, 11: 256.
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