A large-scale international collaboration called MEGASTROKE has identified 22 new genetic risk factors for stroke, thus tripling the number of gene regions known to affect stroke risk. The findings, published in the journal Nature Genetics, demonstrate shared genetic influences with multiple related vascular conditions, especially blood pressure, but also coronary artery disease, venous thromboembolism and others. Linking these results with extensive biological databases provides novel clues on stroke mechanisms and illustrates the potential of genetics to identify drug targets for stroke therapy.
Malik et al conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. Image credit: Gerd Altmann.
Stroke has multiple etiologies, but its molecular mechanisms remain poorly understood, which makes developing new treatments challenging.
This genome-wide association study provides extensive novel insight on the biology and pathways leading to stroke.
“Because the extent to which individual variants modify stroke risk is very small, it required a large number of subjects to discover these variants,” said co-lead author Professor Martin Dichgans, director of the Institute for Stroke and Dementia Research at the Ludwig-Maximilians-University, Germany.
“Our group has leveraged extensive datasets set up by numerous researchers over the past few years.”
“We can’t overstate the importance of international collaboration across different ethnic origins when studying genetics of complex, common diseases like stroke. This large-scale collaboration across continents has been a game changer,” added co-lead author Professor Stephanie Debette, from the University of Bordeaux and Bordeaux University Hospital, France.
The study was based on DNA samples of 520,000 European, North- and South American, Asian, African, and Australian participants of whom 67,000 had a stroke.
From the millions of genetic variants analyzed, 32 genomic regions were shown to be associated with stroke of which two thirds are novel.
“The identification of genetic regions that are strongly correlated to stroke will increase potential targets for stroke drug development,” said co-author Dr. Sudha Seshadri, from the University of Texas Health Sciences Center, San Antonio.
Stroke can originate from alterations in various parts of the vasculature including large arteries, small arteries, the heart, and the venous system and the authors found genetic risk factors implicated in each of these mechanisms.
They showed that some genetic risk factors contribute to specific mechanisms and others to stroke susceptibility at large.
The team further found shared genetic influences between stroke caused by vessel occlusion (the most common cause of stroke) and stroke caused by rupture of a blood vessel (the most catastrophic cause of stroke), often thought to have opposite mechanisms.
When the scientists took a closer look on the genomic areas pinpointed in the study, they noticed that several of them overlap with genomic areas known to be implicated in related vascular conditions such as atrial fibrillation, coronary artery disease, venous thrombosis, or vascular risk factors, especially elevated blood pressure, and less so hyperlipidemia.
By adding data on gene expression, protein expression, and other characteristics in multiple cell types and tissues, they obtained first insights into the specific genes, molecular pathways, and cell and tissue types through which the new genetic risk factors cause stroke.
The researchers further found that the genes they identified are enriched in drug targets for antithrombotic therapy, used to re-open occluded blood vessels in patients with acute stroke or to prevent vascular events including stroke.
“These findings illustrate the potential of genetics for drug discovery,” said Dr. Bradford Worrall, a researcher at the University of Virginia School of Medicine.
“Vascular disease in the brain — a series of strokes — can lead to dementia,” Dr. Seshadri said.
“Understanding these newly identified risk factors for stroke should also enable us to find novel treatments for dementia.”
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Rainer Malik et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nature Genetics, published online March 12, 2018; doi: 10.1038/s41588-018-0058-3
