Miller School Helps Provide New Insight into Causes of Stroke in Large International Genetic Study

Top stroke neurologists and researchers at the University of Miami Miller School of Medicine and UHealth — the University of Miami Health System were part of a major international research consortium, studying 520,000 people from around the world, that identified 22 new genetic risk factors for stroke, thus tripling the number of gene regions known to affect stroke risk.

The research consortium identified 22 new genetic risk factors for stroke.

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 were published online in the journal Nature Genetics on March 12. 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.

“This study truly demonstrates the power of collaborative international team science to address complex questions and advance our understanding of stroke,” said study co-author Ralph L. Sacco, M.D., M.S., executive director of the McKnight Brain Institute, professor and chair of neurology, Olemberg Chair in Neurological Disorders, senior associate dean for clinical and translational science and director of UM’s Clinical and Translational Science Institute.

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 has identified new genes that may cause stroke but also other vascular disease such as heart attacks and risk factors such as hypertension,” said co-author Tatjana Rundek, M.D., Ph.D., professor of neurology and public health sciences and executive vice chair for research and faculty affairs in the Department of Neurology. “The discovery of these genes is the first step in understanding their function in stroke and conducting further investigations to devise novel medications for stroke prevention and treatment. These discoveries hold promise to revolutionize how we treat and prevent stroke.”

Rundek, who is also director of the Clinical Translational Research Division in Neurology, and director of the Master of Science Degree in Clinical Translational Investigations, said the large-scale study “is the first step to evaluate functional pathways these genes are part of in order to develop new non-traditional therapeutic targets for stroke and other vascular diseases.”

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.

UM stroke experts contributed to this collaboration by providing clinical and genetic data collected from stroke patients as well as from patients and healthy control subjects from the Miller and Columbia University Medical Schools’ National Institutes of Health-funded Northern Manhattan study. Sacco and Rundek were also members and leaders of the steering and publication committees of the Stroke Genetics Network (SiGN), a project with the NIH/NINDS (National Institute of Neurological Disorders and Stroke) that provided a significant proportion of data from stroke patients and controls for this meta-analysis.

In addition to UM and other investigators in the United States, MEGASTROKE members include research groups from Germany, France, the United Kingdom, Japan, 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 at the University Hospital, Ludwig-Maximilians-University 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,” said Stephanie Debette, professor of epidemiology and neurologist at the University of Bordeaux and Bordeaux University Hospital, leading a research team at INSERM Center U1219, and another leader of the study.

Stroke is the second most common cause of both death and disability-adjusted life-years worldwide, but its molecular mechanisms remain poorly understood, which makes developing new treatments challenging. This study provides extensive novel insight on the biology and pathways leading to stroke.

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 at 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 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, the researchers said.

These genetic findings represent a first step toward developing personalized, 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 novel drug targets.

These findings — linking stroke with multiple other disease states and with dysregulation of genes, proteins, and molecular pathways in specific cell types and organs — were generated using novel bioinformatics approaches that utilize and combine information from various international biological databases. Such datasets are invaluable in situations like this when tissue samples from patients are not readily available, underscoring the importance of data sharing.