阻塞性睡眠呼吸暂停与脑成像衍生表型的双向孟德尔随机化研究

doi:10.3969/j.issn.1674-8115.2025.04.009

摘要/Abstract

摘要：

目的·通过两样本孟德尔随机化（Mendelian randomization，MR）研究阐述阻塞性睡眠呼吸暂停（obstructive sleep apnea，OSA）与脑成像衍生表型（imaging-derived phenotype，IDP）之间的因果关系。方法·OSA的相关遗传数据来自芬兰基因生物银行R11（FinnGen Biobank）中的全基因组关联研究（genome⁃wide association study，GWAS），其中，病例组50 200例，对照组401 484例；从中筛选出27个单核苷酸多态性（single⁃nucleotide polymorphism，SNP）作为OSA的工具变量。3 935种IDP的GWAS来自英国生物样本库（UK Biobank）39 691名欧洲血统个体的多模态神经影像数据。采用逆方差加权（inverse variance weighted，IVW）为主的多种MR方法进行分析，并进行异质性、多效性和敏感性检验。结果·MR分析显示8种IDP与OSA的发生显著相关，例如右侧半球额中回尾部体积显著增加OSA风险，体积每增加1个标准差对应于OSA风险增高11% （IVW方法的OR=1.11，95%CI 1.06~1.17，P<0.001）。而OSA可能与1种IDP呈负相关（IVW β=-0.10，95%CI -0.19~-0.01，P=0.025）。这种IDP属于静息态功能连接特征，是双侧额极与右侧额顶皮层的功能连接强度。异质性检验提示工具变量之间未发现显著异质性，多效性检验未检测到多效性，敏感性分析提示结果稳定。结论·8种IDP可能与OSA的发生显著相关，而其中1种IDP与OSA的发生呈负相关，为非侵入式神经调控治疗OSA提供了潜在靶点。

关键词: 睡眠呼吸暂停, 孟德尔随机化, 神经影像

Abstract:

Objective ·To elucidate the causal relationship between obstructive sleep apnea (OSA) and imaging-derived phenotypes (IDPs) through two-sample Mendelian randomization (MR) studies. Methods ·The genetic data related to OSA were obtained from the genome-wide association study (GWAS) (n_{case group}=50 200, n_{control group}=401 484) in the FinnGen Biobank R11. Twenty-seven single nucleotide polymorphisms (SNPs) were screened out as instrumental variables of OSA. The GWAS of 3 935 IDPs was based on multimodal neuroimaging data from 39 691 individuals of European ancestry in the UK Biobank. Multiple MR methods, primarily utilizing inverse variance weighted (IVW) analysis, were applied, along with assessments for heterogeneity, pleiotropy, and sensitivity. Results ·MR analysis indicated that 8 IDPs were associated with OSA. For example, the genetically determined volume of caudal middle frontal gyrus in the right hemisphere was associated with an increased risk of OSA. A one‒standard-deviation increase in volume corresponded to an 11% higher risk of OSA (IVW OR=1.11, 95%CI 1.06‒1.17, P<0.001). Genetically determined reduced risk of OSA was associated with a resting-state functional connectivity characteristic (IVW β=-0.10, 95%CI -0.19‒-0.01, P=0.025), representing the functional connectivity strength between the bilateral frontal poles and the right frontal-parietal cortex. The heterogeneity test did not find significant heterogeneity among the instrumental variables. The pleiotropy test did not detect any pleiotropy. The sensitivity analysis indicated stable results. Conclusion ·Eight IDPs may have a causal relationship with the occurrence of OSA, among which one IDP shows a bidirectional causal relationship, providing potential targets for non-invasive neuromodulation interventions in OSA.

Key words: sleep apnea, Mendelian randomization (MR), neuroimaging

中图分类号:

R762

张慧华, 干静, 侯媌媌, 卢娜. 阻塞性睡眠呼吸暂停与脑成像衍生表型的双向孟德尔随机化研究[J]. 上海交通大学学报（医学版）, 2025, 45(4): 468-475.

ZHANG Huihua, GAN Jing, HOU Miaomiao, LU Na. Bidirectional Mendelian randomization study of the relationship between brain imaging-derived phenotypes and obstructive sleep apnea[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(4): 468-475.

图/表 7

图1 IDP与OSA双向MR分析流程Note： 1—Relevance assumption (the selected instrumental variables must be associated with the exposure); 2—Independence assumption (the selected instrumental variables were not associated with potential confounders); 3—Exclusion restriction assumption (the instrumental variables affected the outcome only through their effect on the exposure). IV—instrumental variable.

Fig 1 Workflow of bidirectional MR analysis between IDPs and OSA

图2 IDP对OSA的MR估计值

Fig 2 MR estimates of the effects of IDPs on OSA

图3 IDP与OSA的遗传关联效应散点图Note： A. Scatterplot of SNP effects on IDP 2895 and OSA. B. Scatterplot of SNP effects on IDP 5781 and OSA. C. Scatterplot of SNP effects on IDP 4132 and OSA. D. Scatterplot of SNP effects on IDP 4350 and OSA. E. Scatterplot of SNP effects on IDP IDP 4390 and OSA. F. Scatterplot of SNP effects on IDP 2991 and OSA. G. Scatterplot of SNP effects on IDP 3078 and OSA. H. Scatterplot of SNP effects on IDP 6296 and OSA. I. Scatterplot of SNP effects on OSA and IDP 6296.

Fig 3 Scatterplots of genetic association effects between IDPs and OSA

图4 8种IDP示意图

Fig 4 Diagram of the 8 IDPs

图5 不同MR分析方法检验IDP对OSA的关联效应

Fig 5 Causal associations between IDPs and OSA in the forward and reverse MR with different MR analysis methods

图6 IDP与OSA关联的SNP效应漏斗图Note： A. Funnel plot of the effect of IDP 2895 on OSA. B. Funnel plot of the effect of IDP 5781 on OSA. C. Funnel plot of the effect of IDP 4132 on OSA. D. Funnel plot of the effect of IDP 4350 on OSA. E. Funnel plot of the effect of IDP 4390 on OSA. F. Funnel plot of the effect of IDP 2991 on OSA. G. Funnel plot of the effect of IDP 3078 on OSA. H. Funnel plot of the effect of IDP 6296 on OSA. I. Funnel plot of the effect of OSA on IDP 6296. IV—instrumental variable.

Fig 6 Funnel plot of SNP effects on IDP-OSA associations

图7 OSA对IDP的MR估计值

Fig 7 MR estimates of the effects of OSA on IDPs

参考文献 23

1	中华耳鼻咽喉头颈外科杂志编辑委员会咽喉组, 中华医学会耳鼻咽喉头颈外科学分会咽喉学组、嗓音学组, 上海交通大学医学院附属第六人民医院, 等. 成人阻塞性睡眠呼吸暂停诊断和外科治疗指南(2024)计划书[J]. 中华耳鼻咽喉头颈外科杂志, 2024, 59(2): 114-121.
	Subspecialty Group of Laryngopharyngology, Editorial Board of Chinese Journal of Otorhinolaryngology Head and Neck Surgery, Subspecialty Group of Laryngopharyngology, Society of Otorhinolaryngology Head and Neck Surgery, Chinese Medical Association, Subspecialty Group of Voice, Society of Otorhinolaryngology Head and Neck Surgery, Chinese Medical Association, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, et al. Guideline for the diagnosis and surgical treatment of adult obstructive sleep apnea (2024): a protocol[J]. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 2024, 59(2): 114-121.
2	BENJAFIELD A V, AYAS N T, EASTWOOD P R, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis[J]. Lancet Respir Med, 2019, 7(8): 687-698.
3	WEIHS A, FRENZEL S, WITTFELD K, et al. Associations between sleep apnea and advanced brain aging in a large-scale population study[J]. Sleep, 2021, 44(3): zsaa204.
4	HUANG X, TANG S, LYU X J, et al. Structural and functional brain alterations in obstructive sleep apnea: a multimodal meta-analysis[J]. Sleep Med, 2019, 54: 195-204.
5	KARIMI M, HEDNER J, HÄBEL H, et al. Sleep apnea-related risk of motor vehicle accidents is reduced by continuous positive airway pressure: Swedish Traffic Accident Registry data[J]. Sleep, 2015, 38(3): 341-349.
6	SEKULA P, FABIOLA GRECO M, PATTARO C, et al. Mendelian randomization as an approach to assess causality using observational data[J]. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
7	Oxford Centre for Functional MRI of the Brain (FMRIB/WIN), Oxford University on behalf of UK Biobank. UK Biobank brain imaging documentation [EB/OL]. [2024-05-10]. https://biobank.ctsu.ox.ac.uk/crystal/crystal/docs/brain_mri.pdf.
8	GUO X M, WANG D K, YING C D, et al. Association between brain structures and migraine: a bidirectional Mendelian randomization study[J]. Front Neurosci, 2023, 17: 1148458.
9	WILLIAMS J A, BURGESS S, SUCKLING J, et al. Inflammation and brain structure in schizophrenia and other neuropsychiatric disorders: a mendelian randomization study[J]. JAMA Psychiatry, 2022, 79(5): 498-507.
10	BOWDEN J, DEL GRECO M F, MINELLI C, et al. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization[J]. Stat Med, 2017, 36(11): 1783-1802.
11	HARTWIG F P, DAVEY SMITH G, BOWDEN J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption[J]. Int J Epidemiol, 2017, 46(6): 1985-1998.
12	BARIL A A, MARTINEAU-DUSSAULT M È, SANCHEZ E, et al. Obstructive sleep apnea and the brain: a focus on gray and white matter structure[J]. Curr Neurol Neurosci Rep, 2021, 21(3): 11.
13	HUANG Y J, SHEN C, ZHAO W, et al. Genes associated with altered brain structure and function in obstructive sleep apnea[J]. Biomedicines, 2023, 12(1): 15.
14	LI M X, YAN C Y, WANG S. New insights on the role of the insular cortex and habenula in OSA[J]. Sleep Breath, 2015, 19(4): 1347-1353.
15	LEE M H, SIN S, LEE S, et al. Altered cortical structure network in children with obstructive sleep apnea[J]. Sleep, 2022, 45(5): zsac030.
16	DELAVEAU P, ARRUDA SANCHEZ T, STEFFEN R, et al. Default mode and task-positive networks connectivity during the N-Back task in remitted depressed patients with or without emotional residual symptoms[J]. Hum Brain Mapp, 2017, 38(7): 3491-3501.
17	ZHANG Q, WANG D W, QIN W, et al. Altered resting-state brain activity in obstructive sleep apnea[J]. Sleep, 2013, 36(5): 651-659B.
18	万晓勇, 赵文瑞, 吴欣然, 等. 阻塞性睡眠呼吸暂停的脑影像研究: 来自静息态脑电和功能磁共振的证据[J]. 生理学报, 2019, 71(5): 760-768.
	WAN X Y, ZHAO W R, WU X R, et al. The brain imaging studies of obstructive sleep apnea: evidence from resting-state EEG and fMRI[J]. Acta Physiologica Sinica, 2019, 71(5): 760-768.
19	CHEN L T, FAN X L, LI H J, et al. Topological reorganization of the default mode network in severe male obstructive sleep apnea[J]. Front Neurol, 2018, 9: 363.
20	WEN X T, LIU Y J, YAO L, et al. Top-down regulation of default mode activity in spatial visual attention[J]. J Neurosci, 2013, 33(15): 6444-6453.
21	CHEN A C, OATHES D J, CHANG C T, et al. Causal interactions between fronto-parietal central executive and default-mode networks in humans[J]. Proc Natl Acad Sci USA, 2013, 110(49): 19944-19949.
22	FOX M D, SNYDER A Z, VINCENT J L, et al. The human brain is intrinsically organized into dynamic, anticorrelated functional networks[J]. Proc Natl Acad Sci USA, 2005, 102(27): 9673-9678.
23	CHEN L T, FAN X L, LI H J, et al. Aberrant brain functional connectome in patients with obstructive sleep apnea[J]. Neuropsychiatr Dis Treat, 2018, 14: 1059-1070.

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