Causal Relations Between Obstructive Sleep Apnea and Stroke: A Mendelian Randomization Study

Figures & data

Figure 1 The overview and assumptions of the MR study design. Assumption 1: the instrumental variables that refer to genetic variation have a strong relationship with exposure (OSA). Assumption 2: the used IVs are not linked with potential confounders. Assumption 3: the genetic variants are related to the outcome only through selected exposure (OSA), not via alternative pathways.

Table 1 Details of the GWAS Databases Included in the Mendelian Randomization

Phenotype	Consortium	Participants (Cases/Controls)	Ancestry	PubMed ID
Obstructive sleep apnea	FINNGen	16,761/201,194	European	33243845
Stroke	MEGASTROKE	40,585/406,111	European	29531354
Ischemic stroke	MEGASTROKE	34,217/ 406,111	European	29531354
Large vessel ischemic stroke	MEGASTROKE	4373/406,111	European	29531354
Cardioembolic ischemic stroke	MEGASTROKE	7193/406,111	European	29531354
Small vessel ischemic stroke	MEGASTROKE	5386/192,662	European	29531354
Lacunar stroke	ISGC	6030/248,929	European	33773637
Intracerebral hemorrhage	ISGC	1545/1481	European	24656865

Note: Data summarized from GWAS databases from IEU OpenGWAS database (https://gwas.mrcieu.ac.uk/). Abbreviations: FINNGen, Finnish Gene; ISGC, International Stroke Genetics Consortium.

Table 2 Characteristics of Instrumental Variables Associated with Obstructive Sleep Apnea

SNP	Chr	Genes	EA/OA	EAF	Beta	SE	P value	F
rs9937053	16	FTO	A/G	0.43	0.1020	0.0125	4.3×10^−16	66.6
rs10507084	12	RMST	T/C	0.18	0.1085	0.0163	2.8×10^−11	44.3
rs142006783	16	RFWD3	C/T	0.04	0.1783	0.0327	4.8×10^−8	29.7
rs4837016	9	GAPVD1	A/G	0.47	−0.0706	0.0125	1.5×10^−8	31.9
rs10928560	2	CXCR4	T/C	0.19	−0.0878	0.0158	2.8×10^−8	30.9

Abbreviations: SNP, single nucleotide polymorphisms; EAF, EA/OA, effect allele/other allele; effect allele frequency; SE, standard error; F, F statistics value.

Table 3 MR Analyses Effect Estimates for Associations Between Obstructive Sleep Apnea and Stroke

Phenotype	nSNPs	OR (95% CI)	P	Q/p	P for MR-Egger Intercept	P for MR-PRESSO Global Test
Stroke
IVW	4	0.99 (0.81, 1.21)	0.909	5.11/0.164	0.021/0.690	0.310
MR Egger regression	4	0.77 (0.27, 2.26)	0.684
Weighted median	4	0.99 (0.81, 1.20)	0.907
Weighted mode	4	1.00 (0.81, 1.22)	0.982
Ischemic stroke	4
IVW	4	1.01 (0.82, 1.23)	0.927	4.51/0.212	0.040/0.422	0.387
MR Egger regression	4	0.63 (0.25, 1.61)	0.439
Weighted median	4	1.05 (0.86, 1.28)	0.645
Weighted mode	4	1.05 (0.86, 1.29)	0.647
Large vessel ischemic stroke	4
IVW	4	1.05 (0.73, 1.51)	0.795	4.202/0.240	−0.131/0.195	0.327
MR Egger regression	4	4.62 (0.98, 21.79)	0.192
Weighted median	4	1.22 (0.81, 1.84)	0.348
Weighted mode	4	1.28 (0.79, 2.07)	0.392
Cardioembolic ischemic stroke	4
IVW	4	1.03 (0.74, 1.43)	0.855	3.182/0.364	−0.028/0.742	0.436
MR Egger regression	4	1.43 (0.25, 8.30)	0.726
Weighted median	4	1.03 (0.69, 1.53)	0.899
Weighted mode	4	1.01 (0.65, 1.56)	0.982
Small vessel ischemic stroke
IVW	3	1.13 (0.88, 1.46)	0.329	0.304/0.859	0.034/0.682	–
MR Egger regression	3	0.77 (0.18, 3.21)	0.777
Weighted median	3	1.14 (0.84, 1.54)	0.403
Weighted mode	3	1.16 (0.81, 1.65)	0.511
Lacunar stroke	4
IVW	4	1.07 (0.74, 1.56)	0.721	3.118/0.373	0.024/0.808	0.465
MR Egger regression	4	0.81 (0.11, 6.07)	0.858
Weighted median	4	1.06 (0.68, 1.66)	0.800
Weighted mode	4	1.08 (0.66, 1.78)	0.774
Intracerebral hemorrhage
Wald ratio	1	0.37 (0.09, 1.48)	0.160	–	–	–

Abbreviations: nSNPs, number of single nucleotide polymorphisms; OR, odds ratio; CI, confidence interval; Q, Cochran Q-test; IVW, inverse-variance weighted.

Figure 2 Scatter plots of genetic associations between OSA and stroke or subtypes. (A) Stroke; (B) ischemic stroke; (C) large vessel stroke; (D) cardioembolic stroke; (E) small vessel stroke; (F) lacunar stroke. The slope of the straight line indicates the magnitude of the causal association.

Abbreviations: OSA, obstructive sleep apnea; SNP, single nucleotide polymorphism; MR, Mendelian randomization.

Figure 3 Forest plot of genetic associations between OSA and stroke or subtypes. (A) Stroke; (B) ischemic stroke; (C) large vessel stroke; (D) cardioembolic stroke; (E) small vessel stroke; (F) lacunar stroke.

Abbreviation: OSA, obstructive sleep apnea.

Figure 4 The leave-one-out-sensitivity forest plot of genetic associations between OSA and stroke or subtypes. (A) Stroke; (B) ischemic stroke; (C) large vessel stroke; (D) cardioembolic stroke; (E) small vessel stroke; (F) lacunar stroke. The bars indicate the CI.

Abbreviation: OSA, obstructive sleep apnea.