By Jean Balchin 19/03/2018


An large-scale international genetic study on stroke, based on DNA samples of 520,000 people has identified 22 new genetic risk factors for stroke. Published recently in the journal Nature Geneticsthe study’s participants originated from Europe, North and South America, Asia, Africa and Australia, and were compiled from 29 large studies. 67,000 participants in the study had suffered a stroke.

From the millions of genetic variants analysed, 32 independent genomic regions were identified to be associated with stroke. Two thirds of these genomic regions were hitherto not known to be associated with stroke.

According to Martin Dichgans, professor of neurology and director at the Institute for Stroke and Dementia Research, Ludwig-Maximilians-University in Munich, and one of the leaders of the current study:

“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.”

Additionally, according to Stephanie Debette, Professor of Epidemiology and Neurologist at University of Bordeaux and Bordeaux University Hospital, and another leader of the 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.”

Although stroke is the second most common cause of both death and disability-adjusted life-years worldwide, its molecular mechanisms remain poorly understood. This means that developing new treatments for stroke is a very challenging process. However, this study provides extensive new insights on the biology and pathways leading to stroke.

A stroke is essentially an attack to the brain, and can happen to anyone at any time. It occurs when blood flow to an area of the brain is obstructed, causing the brain cells to be deprived of oxygen and die. The abilities controlled by that area of the brain are correspondingly lost. The nature of a stroke’s effect depends on where the stroke occurs in the brain, and how much of the brain is damaged. There are two main types of strokes; hemorrhagic and ischemic. A hemorrhagic stroke occurs when a brain aneurysm bursts or a weakened blood vessel leaks. This is the least common type of stroke, but most often results in death. Ischemic strokes occur when a blood vessel carrying blood to the brain is blocked by a blood clot.

Stroke can originate from alterations in various parts of the vasculature including large arteries, small arteries, the heart and the venous system. This study revealed that genetic risk factors implicated in each of these mechanisms. The researchers showed that some genetic risk factors contribute to specific mechanisms and others, to stroke susceptibility at large.

It was also discovered that there existed shared genetic influences between stroke caused by vessel occlusion (ie ischemic strokes, the most common cause of stroke) and stroke caused by rupture of a blood vessel (ie hemorrhagic strokes, the most catastrophic cause of stroke), often thought to have opposite mechanisms. There was also considerable 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 compiled by their co-investigators, the researchers 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, says Professor Jane Maguire, a researcher from University of Technology Sydney and co-author of the study.

“These genetic findings represent a first step towards developing personalised, evidence-based treatments for this very complex disease. They provide evidence for several novel biological pathways involved in stroke that may lead to the discovery of new drug targets,” says Professor Maguire, a former chair of the International Stroke Genetics Consortium.

These fascinating findings were generated using new and creative bioinformatics approaches that utilize and combine information from various international biological databases. These datasets are incredibly helpful in situations like this when tissue samples from patients are not readily available.

The study received financial support from multiple sources, including from the National Health and Medical Research Council (NHMRC). It was conducted by members of MEGASTROKE, a large-scale international collaboration launched by the International Stroke Genetics Consortium, a multi-disciplinary collaborative of experts in stroke genetics who have been working together for the past 10 years. 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.

You can read the study here.