Mendelian randomization studies on ischemic stroke: a field synopsis and systematic review

Area of Science:

• Epidemiology
• Genetics
• Neurology

Background:

• Ischemic stroke (IS) is a leading global cause of death and disability.
• Previous observational studies have limitations in establishing causality for IS risk factors.
• Mendelian randomization (MR) studies offer a powerful approach to investigate genetic causality, but results are often inconsistent.

Purpose of the Study:

• To systematically review and evaluate the strength of evidence from published MR studies on causal relationships between exposures and IS and its subtypes.
• To identify robust causal determinants of IS risk and subtypes.
• To provide insights for developing effective IS prevention strategies.

Main Methods:

• Comprehensive literature search of PubMed and Embase databases for MR studies on IS and its subtypes.
• Summation and classification of MR results into four grades based on evidence strength (significance, concordance, sensitivity analyses).
• Inclusion of 207 studies with 1199 MR associations for analysis.

Main Results:

• Identified 89 causal relationships with convincing evidence.
• Robust causal determinants for IS susceptibility include genetically predicted diastolic blood pressure, type 2 diabetes, Parkinson's disease, and primary aldosteronism.
• Specific findings for IS subtypes: higher vitamin K1 levels linked to large artery stroke, primary aldosteronism to small vessel stroke, and adult height to both lower risk of small vessel stroke and higher risk of cardioembolic stroke.

Conclusions:

• This systematic review provides a robust summary and evaluation of MR evidence for IS causality.
• Identified 89 convincing causal relationships between various exposures and IS or its subtypes.
• Results offer valuable insights for future research and the development of targeted IS prevention strategies.