Large-scale genetic study provides new insight into the causes of stroke
An international research consortium studying 520,000 individuals from around the world has identified 22 new genetic risk factors for stroke, thus tripling the number of gene regions known to affect stroke risk. “A first step towards developing more personalized treatments”, says co-author Christina Jern, Professor at Sahlgrenska Academy.
The results 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.
The results of the largest genetic study on stroke thus far has been published in the journal Nature Genetics. 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. These were derived from 29 large studies.
From the millions of genetic variants analyzed, 32 independent genomic regions were shown to be associated with stroke of which two thirds are novel.
The study was conducted by members of Megastroke, a large-scale international collaboration launched by the International Stroke Genetics Consortium, an international multi-disciplinary collaborative of experts in stroke genetics from around the world who have been working together for the past 10 years.
Researchers in 20 countries
Megastroke members include research groups from Germany, France, the UK, Japan, USA, Iceland, Spain, Switzerland, Italy, Belgium, the Netherlands, Denmark, Sweden, Norway, Finland, Estonia, Poland, Singapore, Australia, and Canada.
”Because the extent to which individual variants modify stroke risk is very small, it required a large number of subjects to discover these variants. Our group has leveraged extensive datasets set up by numerous researchers over the past few years”, said Martin Dichgans, Professor of Neurology and Director at the Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, and one of the leaders of the current study.
“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”, says Stephanie Debette, Professor of Epidemiology and Neurologist at University of Bordeaux and Bordeaux University Hospital, leading a research team at INSERM Center U1219, and another leader of the study.
Global burden of stroke
Stroke is the most common cause of adult disability, the second most common cause of death, and a major cause of health care expenditures and loss of quality-adjusted life years. Each year, approximately 17 million people suffer from stroke worldwide, of which 25,000 affects people in Sweden. The cost due to stroke in Sweden is approximately 18 billions Swedish crowns every year.
Stroke can originate from alterations in various parts of the vasculature including large arteries, small arteries, the heart, and the venous system and the researchers 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. They 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 researchers 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.
Precision medicine
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.
“The results from Megastroke provide evidence for several novel biological pathways involved in stroke that may lead to the discovery of novel drug targets”, says Professor Christina Jern, Sahlgrenska Academy at University of Gothenburg, one of the co-authors of the study. “Our research group has for many years studied the importance of hemostasis in ischemic stroke, and therefore finds the results of genetic overlap with thromboembolism and overrepresentation of variants in genes of importance for blood clotting very interesting”, she says. “In the long run, the results can be a first step towards developing more tailor-made treatments, in other words precision medicine, for this complex disease.”
The cohort from the Gothenburg site, the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), PI Christina Jern, received financial support from multiple sources including the Swedish Research Council, the Swedish Heart-Lung foundation, STROKE-Riksförbundet and ALF.
Contact: Christina Jern
Illustrations: Pictures of DNA sequences, brain etc (Matton images, Mostphotos) and portrait picture of Christina Jern (photo: Cecilia Hedström)