MEGASTROKE Study Identifies 22 New Genetic Risk Factors for Stroke

A large international genetic study led by researchers involved in the MEGASTROKE collaboration, and published in Nature Genetics, has identified 22 previously unknown genetic loci associated with stroke. The analysis compared DNA from more than 520,000 people worldwide, including 67,162 people who had experienced a stroke and 454,450 control subjects, to reveal genetic variants that influence stroke risk across multiple stroke subtypes.

Study Design and Scope

The multi-ancestry genome-wide association meta-analysis examined the genomes of 521,612 individuals to discover genetic regions linked to stroke and its subtypes. This large sample size gave the team the statistical power to detect 22 new risk loci, bringing the total number of stroke-associated genetic loci identified to 32. Researchers evaluated associations with overall stroke as well as specific etiological subtypes, using extensive bioinformatics analyses and functional datasets to prioritize the most likely causal variants and genes.

Key Findings

About one third of the newly identified variants appear to increase stroke risk indirectly by raising blood pressure, a well-established risk factor for cerebrovascular disease. The remaining loci point to biological mechanisms not previously implicated in stroke, offering fresh insights into disease pathways. Notably, one gene was associated with increased risk for both haemorrhagic stroke—where a blood vessel ruptures and bleeds into the brain—and ischaemic stroke—caused when blood flow to the brain is blocked by a clot. That overlap suggests the potential to develop therapies that reduce the risk of multiple common stroke types.

The study also uncovered shared genetic variation between stroke and related vascular traits, including blood pressure regulation, cardiac traits, and venous thromboembolism. At least 18 loci showed overlap with these vascular traits. Genetic risk scores and linkage-disequilibrium-score regression supported these shared relationships and helped clarify how specific loci contribute to stroke subtypes.

Implications for Treatment and Prevention

Because several identified loci map to genes and pathways with known drug targets, the results are of strong translational interest. The study found significant enrichment of stroke risk loci among targets relevant to antithrombotic therapy, indicating that existing drug classes or new drugs targeting these pathways could potentially be repurposed or developed to prevent stroke. By illuminating biological mechanisms that underlie stroke susceptibility, the findings provide a roadmap for future therapeutic research and precision prevention strategies.

Clinical and Public Health Context

Stroke remains a major cause of death and disability. In the UK alone there are more than 100,000 strokes each year, with an associated health-care cost estimated at around £2 billion. Stroke causes approximately 38,000 deaths annually in the UK and leaves about 1.2 million people living with long-term disability from stroke. Improved understanding of genetic risk could help identify individuals at higher risk and guide the development of new treatments aimed at preventing these devastating outcomes.

Researcher Comments

Associate Professor Jemma Hopewell, BHF Research Fellow at the University of Oxford and one of the study authors, said that stroke is a leading cause of death and disability worldwide and that its underlying causes are still not well understood, which has hindered the development of new therapies. She noted that this study brings researchers one step closer to identifying treatments that could reduce stroke risk.

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, commented that a clearer understanding of genetic risk factors will help prevent stroke and support the development of urgently needed new treatments. He emphasized that, despite advances such as clot-busting drugs and clot retrieval devices, treatment and prevention options remain limited and that these results offer renewed hope.

brain scan — The researchers believe this discovery could help drive development of new drugs that reduce the risk of both haemorrhagic and ischaemic stroke. Image adapted from the University of Oxford news release.

About the Research

Title: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Abstract summary: The multiancestry genome-wide association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) identified 22 new stroke risk loci. Shared genetic variation was found with related vascular traits including blood pressure, cardiac traits, and venous thromboembolism at individual loci and via genetic risk scores and linkage-disequilibrium-score regression. Multiple loci showed distinct association and pleiotropy patterns across etiological stroke subtypes. Eleven new susceptibility loci point to mechanisms not previously implicated in stroke pathophysiology, with candidate risk variants and genes prioritized through bioinformatics analyses and functional datasets. Stroke risk loci were significantly enriched among drug targets for antithrombotic therapy.

Source: University of Oxford. Publisher: Organized by NeuroscienceNews.com. Original research published in Nature Genetics (doi 10.1038/s41588-018-0058-3).