Skip to main content
SpringerLink
Log in

Correlation between obstructive sleep apnea and cerebral small vessel disease: a mendelian randomization study

  • Research Article
  • Published:
Genes & Genomics Aims and scope Submit manuscript

Abstract

Background

Whether obstructive sleep apnea (OSA) is causally associated with an increased risk of cerebral small vessel disease (CSVD) remains controversial. We conducted a two-sample Mendelian randomization (MR) study to clarify the causal relationship between OSA and CSVD risk.

Methods

Single-nucleotide polymorphisms associated with OSA at the genome-wide significance level (P < 5 × 10− 8) in the FinnGen consortium were selected as instrumental variables. Summary-level data for white matter hyperintensities (WMHs), lacunar infarctions (LIs), cerebral microbleeds (CMBs), fractional anisotropy (FA), and mean diffusivity (MD) were obtained from three meta-analyses of genome-wide association studies (GWASs). The random-effects inverse-variance weighted (IVW) method was selected for the major analysis. Weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses.

Results

Genetically predicted OSA was not associated with LIs (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.86–1.40), WMHs (OR = 0.94, 95% CI = 0.83–1.07), FA (OR = 1.33, 95% CI = 0.75–2.33), MD (OR = 0.93, 95% CI = 0.58–1.47), CMBs (OR = 1.29, 95% CI = 0.86–1.94), mixed CMBs (OR = 1.17, 95% CI = 0.63–2.17), and lobar CMBs (OR = 1.15, 95% CI = 0.75–1.76) in IVW method. The results of the sensitivity analyses were generally consistent with the major analyses.

Conclusions

This MR study does not support causal associations between OSA and the risk of CSVD in individuals of European ancestry. These findings need to be further validated in randomized controlled trials, larger cohort studies, and MR studies based on larger GWASs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

Summary-level data for lacunar stroke are publicly available (PMID: 33773637, https://cd.hugeamp.org/); Summary-level data for white matter hyperintensities, fractional anisotropy, and mean diffusivity are publicly available (PMID: 32358547, https://cd.hugeamp.org/); Summary-level data for cerebral microbleeds are publicly available (PMID: 32913026, https://cd.hugeamp.org/); FinnGen consortium data are available through application (https://r8.finngen.fi/).

References

  • Akoudad S, Wolters FJ, Viswanathan A et al (2016) Association of Cerebral Microbleeds with Cognitive decline and Dementia. JAMA Neurol 73:934–943

    Article  PubMed  PubMed Central  Google Scholar 

  • Alvarez-Sabín J, Romero O, Delgado P et al (2018) Obstructive sleep apnea and silent cerebral infarction in hypertensive individuals. J Sleep Res 27:232–239

    Article  PubMed  Google Scholar 

  • Birnefeld J, Wåhlin A, Eklund A et al (2020) Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA: a 4D flow MRI study. J Neurol 267:721–730

    Article  CAS  PubMed  Google Scholar 

  • Bowden J, Davey Smith G, Burgess S (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44:512–525

    Article  PubMed  PubMed Central  Google Scholar 

  • Bowden J, Davey Smith G, Haycock PC et al (2016) Consistent estimation in mendelian randomization with some Invalid Instruments using a weighted median estimator. Genet Epidemiol 40:304–314

    Article  PubMed  PubMed Central  Google Scholar 

  • Burgess S, Thompson SG (2015) Mendelian randomization: methods for using genetic variants in causal estimation. CRC Press

  • Burgess S, Davies NM, Thompson SG (2016) Bias due to participant overlap in two-sample mendelian randomization. Genet Epidemiol 40:597–608

    Article  PubMed  PubMed Central  Google Scholar 

  • Burgess S, Bowden J, Fall T et al (2017) Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology 28:30–42

    Article  PubMed  Google Scholar 

  • Cai M, Jacob MA, van Loenen MR et al (2022) Determinants and temporal Dynamics of Cerebral Small Vessel Disease: 14-Year Follow-Up. Stroke 53:2789–2798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castronovo V, Scifo P, Castellano A et al (2014) White matter integrity in obstructive sleep apnea before and after treatment. Sleep 37:1465–1475

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen HL, Lu CH, Lin HC et al (2015) White matter damage and systemic inflammation in obstructive sleep apnea. Sleep 38:361–370

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen X, Wang J, Shan Y et al (2019) Cerebral small vessel disease: neuroimaging markers and clinical implication. J Neurol 266:2347–2362

    Article  PubMed  Google Scholar 

  • Cho ER, Kim H, Seo HS et al (2013) Obstructive sleep apnea as a risk factor for silent cerebral infarction. J Sleep Res 22:452–458

    Article  PubMed  Google Scholar 

  • Choi KM, Thomas RJ, Yoon DW et al (2016) Interaction between Obstructive Sleep Apnea and shortened telomere length on Brain White Matter Abnormality. Sleep 39:1639–1645

    Article  PubMed  PubMed Central  Google Scholar 

  • Croall ID, Tozer DJ, Moynihan B et al (2018) Effect of Standard vs intensive blood pressure control on cerebral blood Flow in Small Vessel Disease: the PRESERVE Randomized Clinical Trial. JAMA Neurol 75:720–727

    Article  PubMed  PubMed Central  Google Scholar 

  • De Silva TM, Faraci FM (2020) Contributions of aging to Cerebral Small Vessel Disease. Annu Rev Physiol 82:275–295

    Article  PubMed  Google Scholar 

  • Del Brutto OH, Mera RM, Zambrano M et al (2017) Relationship between obstructive sleep apnea and neuroimaging signatures of cerebral small vessel disease in community-dwelling older adults. The Atahualpa Project Sleep Med 37:10–12

    Article  PubMed  Google Scholar 

  • Edwards BA, Wellman A, Sands SA et al (2014) Obstructive sleep apnea in older adults is a distinctly different physiological phenotype. Sleep 37:1227–1236

    Article  PubMed  PubMed Central  Google Scholar 

  • Gottlieb DJ, Punjabi NM (2020) Diagnosis and management of obstructive sleep apnea: a review. JAMA 323:1389–1400

    Article  PubMed  Google Scholar 

  • Kepplinger J, Barlinn K, Boehme AK et al (2014) Association of sleep apnea with clinically silent microvascular brain tissue changes in acute cerebral ischemia. J Neurol 261:343–349

    Article  PubMed  Google Scholar 

  • Knol MJ, Lu D, Traylor M et al (2020) Association of common genetic variants with brain microbleeds: a genome-wide association study. Neurology 95:e3331–e3343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koo DL, Kim JY, Lim JS et al (2017) Cerebral microbleeds on MRI in patients with obstructive sleep apnea. J Clin Sleep Med 13:65–72

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumar R, Chavez AS, Macey PM et al (2012) Altered global and regional brain mean diffusivity in patients with obstructive sleep apnea. J Neurosci Res 90:2043–2052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee WJ, Jung KH, Nam HW et al (2021) Effect of obstructive sleep apnea on cerebrovascular compliance and cerebral small vessel disease. PLoS ONE 16:e0259469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li HQ, Feng YW, Yang YX et al (2022) Causal relations between Exposome and Stroke: a mendelian randomization study. J Stroke 24:236–244

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu X, Lam DC, Mak HK et al (2022) Associations of sleep apnea risk and oxygen desaturation indices with cerebral small vessel disease burden in patients with stroke. Front Neurol 13:956208

    Article  PubMed  PubMed Central  Google Scholar 

  • Lutsey PL, Norby FL, Gottesman RF et al (2016) Sleep apnea, sleep duration and brain MRI markers of cerebral vascular disease and Alzheimer’s Disease: the atherosclerosis risk in Communities Study (ARIC). PLoS ONE 11:e0158758

    Article  PubMed  PubMed Central  Google Scholar 

  • Macey PM, Kumar R, Woo MA et al (2008) Brain structural changes in obstructive sleep apnea. Sleep 31:967–977

    PubMed  PubMed Central  Google Scholar 

  • Macey PM, Kumar R, Yan-Go FL et al (2012) Sex differences in white matter alterations accompanying obstructive sleep apnea. Sleep 35:1603–1613

    Article  PubMed  PubMed Central  Google Scholar 

  • Nasrallah IM, Pajewski NM, Auchus AP et al (2019) Association of Intensive vs Standard blood pressure control with cerebral White Matter Lesions. JAMA 322:524–534

    Article  PubMed  PubMed Central  Google Scholar 

  • Pasi M, van Uden IW, Tuladhar AM et al (2016) White Matter Microstructural damage on Diffusion Tensor Imaging in Cerebral Small Vessel Disease: clinical consequences. Stroke 47:1679–1684

    Article  PubMed  Google Scholar 

  • Persyn E, Hanscombe KB, Howson JMM et al (2020) Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants. Nat Commun 11:2175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petrea RE, O’Donnell A, Beiser AS et al (2020) Mid to Late Life Hypertension Trends and Cerebral Small Vessel Disease in the Framingham Heart Study. Hypertension 76:707–714

    Article  CAS  PubMed  Google Scholar 

  • Schammel NC, VandeWater T, Self S et al (2022) Obstructive sleep apnea and white matter hyperintensities: correlation or causation? Brain Imaging Behav 16:1671–1683

    Article  PubMed  Google Scholar 

  • Song TJ, Park JH, Choi KH et al (2017) Moderate-to-severe obstructive sleep apnea is associated with cerebral small vessel disease. Sleep Med 30:36–42

    Article  PubMed  Google Scholar 

  • Taylor-Bateman V, Gill D, Georgakis M et al (2021) Cardiovascular Risk factors and MRI markers of Cerebral Small Vessel Disease: a mendelian randomization study. Neurology

  • Traylor M, Persyn E, Tomppo L et al (2021) Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurol 20:351–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Middelaar T, Argillander TE, Schreuder F et al (2018) Effect of Antihypertensive Medication on Cerebral Small Vessel Disease: a systematic review and Meta-analysis. Stroke 49:1531–1533

    Article  PubMed  Google Scholar 

  • Verbanck M, Chen CY, Neale B et al (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases. Nat Genet 50:693–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamashiro K, Tanaka R, Tanaka Y et al (2014) Visceral fat accumulation is associated with cerebral small vessel disease. Eur J Neurol 21:667–673

    Article  CAS  PubMed  Google Scholar 

  • Young T, Peppard PE, Gottlieb DJ (2002) Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 165:1217–1239

    Article  PubMed  Google Scholar 

  • Zacharias HU, Weihs A, Habes M et al (2021) Association between Obstructive Sleep Apnea and Brain White Matter Hyperintensities in a Population-Based cohort in Germany. JAMA Netw Open 4:e2128225

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang DD, Cao Y, Mu JY et al (2022) Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study. Stroke Vasc Neurol 7:302–309

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge all participants and investigators for sharing genome-wide association studies (GWASs) summary-level data.

Funding

None.

Author information

Author notes

  1. Bing Wu and Fang Liu contributed equally to this study.

Authors and Affiliations

  1. Department of Neurology, Army 78th Military Group Hospital, 1 Tian Qing Street, Ai Min District, Mudanjiang, 157000, China

    Bing Wu, Fang Liu, Guiyan Sun & Shuang Wang

Authors
  1. Bing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guiyan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BW, FL, and GYS contributed to the study conception and design. BW, FL, and SW contributed to data acquisition and analysis. BW drafted the manuscript. BW and SW have revised the manuscript. All authors approved the current version of the manuscript for publication.

Corresponding author

Correspondence to Shuang Wang.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest. The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, B., Liu, F., Sun, G. et al. Correlation between obstructive sleep apnea and cerebral small vessel disease: a mendelian randomization study. Genes Genom 45, 1179–1186 (2023). https://doi.org/10.1007/s13258-023-01402-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13258-023-01402-9

Keywords

Search

Navigation