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Ischemic Stroke and Cerebral Microbleeds: A Two-Sample Bidirectional Mendelian Randomization Study
Renjie Liu1, Xin Shi2, Jiahui Feng1
1Department of Neurovascular Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
Introduction:
Recent observational studies have reported the association between ischemic stroke (IS) and cerebral microbleeds (CMBs). Whether this reflects a causal association remains to be established. Herein, we adopted a two-sample bidirectional Mendelian randomization (MR) analysis to comprehensively evaluate the causal association of IS and CMBs.
Methods:
The summary-level genome-wide association studies (GWASs) data of IS were obtained from the GIGASTROKE consortium (62,100 European ancestry cases and 1,234,808 European ancestry controls). All IS cases could be further divided into large-vessel atherosclerosis stroke (LVS, n = 6399), cardio-embolic stroke (CES, n = 10,804) and small-vessel occlusion stroke (SVS, n = 6811). Meanwhile, we used publicly available summary statistics from published GWASs of CMBs (3556 of the 25,862 European participants across 2 large initiatives). A bidirectional MR analysis was conducted using inverse-variance weighting (IVW) as the major outcome, whereas MR-Egger and weighted median (WM) were used to complement the IVW estimates as they can provide more robust estimates in a broader set of scenarios but are less efficient (wider CIs). A Bonferroni-corrected threshold of p < 0.0125 was considered significant, and p values between 0.0125 and 0.05 were considered suggestive of evidence for a potential association.
Results:
We detected that higher risk of IS [IVW odds ratio (OR) 1.47, 95% confidence interval (CI) 1.04-2.07, p = 0.03] and SVS (IVW OR 1.62, 95% CI 1.07-2.47, p = 0.02) were significantly associated with CMBs. Reverse MR analyses found no significant evidence for a causal effect of CMBs on IS and its subtypes.
Conclusions:
Our study provides potential evidence that IS and SVS are causally linked to increased risk of CMBs. Further research is needed to determine the mechanisms of association between IS and CMBs.
Insights
Ischemic stroke (IS) and small-vessel occlusion stroke (SVS) may causally increase the risk of cerebral microbleeds (CMBs). This Mendelian randomization study suggests a potential causal link, warranting further investigation into underlying mechanisms.
Area of Science:
- Neurology
- Genetics
- Epidemiology
Background:
- Observational studies suggest an association between ischemic stroke (IS) and cerebral microbleeds (CMBs).
- The causal relationship between IS and CMBs requires further investigation.
- Mendelian randomization (MR) is a robust method for assessing causality.
Purpose of the Study:
- To evaluate the potential causal association between ischemic stroke (IS) and cerebral microbleeds (CMBs).
- To investigate the causal relationship in a bidirectional manner using genetic data.
- To analyze subtypes of IS, including large-vessel atherosclerosis stroke (LVS), cardio-embolic stroke (CES), and small-vessel occlusion stroke (SVS).
Main Methods:
- A two-sample bidirectional Mendelian randomization (MR) analysis was performed.
- Genome-wide association studies (GWAS) summary statistics for IS (GIGASTROKE consortium) and CMBs were utilized.
- Inverse-variance weighting (IVW), MR-Egger, and weighted median (WM) methods were employed for analysis.
Main Results:
- Higher risk of IS (OR 1.47, p=0.03) and SVS (OR 1.62, p=0.02) were significantly associated with CMBs.
- Reverse MR analyses did not find significant evidence for a causal effect of CMBs on IS or its subtypes.
- A Bonferroni-corrected significance threshold of p<0.0125 was applied.
Conclusions:
- The study provides evidence suggesting a potential causal link between IS, particularly SVS, and an increased risk of CMBs.
- Further research is necessary to elucidate the specific mechanisms underlying the association between IS and CMBs.
- The findings contribute to understanding the complex relationship between cerebrovascular diseases.
