The international research consortium MEGASTROKE, after studying the DNA of 520,000 individuals worldwide, has identified 22 new genetic risk factors for stroke, tripling the number of known genetic regions that influence stroke risk. The work has been led from Spain by Dr. Caty Carrera and Dr. Israel Fernández, researchers from the research group in http://bit.ly/2HsGkPh Neurovascular Diseases at Vall d'Hebron Research Institute (VHIR) and Dr. Jordi Jiménez Conde from the research group in Neurovascular of the Hospital del Mar Institute of Medical Research (IMIM). The results show genetic influences shared with multiple vascular conditions related to stroke, especially blood pressure, but also coronary artery disease or venous thromboembolism, among others. Comparison of these results with extensive biological databases provides new clues about the mechanisms of stroke and illustrates the potential of genetics to identify drug targets for treatment. That is, "the Megastroke study is not just a genetic study, but the most important part of this project has been the discovery of new metabolic pathways that are involved in the risk of developing a stroke. This finding opens up an important new field of study with the aim of finding new therapeutic targets and new drugs to prevent the appearance of this pathology", explained Dr. Israel Fernández. The results of the largest genetic study on stroke carried out so far are published in the online version of the journal Nature Genetics. The study was based on DNA samples from 520,000 European, North American, South American, Asian, African and Australian individuals, 67,000 of whom had a stroke. The participants came from 29 studies.Of the millions of genetic variants analysed, 32 independent genomic regions showed an association with stroke. Two-thirds of them are new, i.e., there was no evidence of their relationship with the pathology. "Since the degree that individual variations modify the risk of stroke is very small, it took a lot of subjects to discover these variants. That's why our group took advantage of the large amount of information created by numerous researchers in recent years," said Martin Dichgans, professor of neurology and director of the Institute for Research on Stroke and Dementia (ISD), University Hospital of Ludwig-Maximilians University (LMU) in Munich. "We cannot exaggerate the importance of international collaboration with regard to different ethnic backgrounds when we study the genetics of complex and common diseases such as stroke. This collaboration on a large scale with all continents has changed the rules of the game," said Stephanie Debette, Professor of epidemiology and Neurology at the University of Bordeaux and Bordeaux University Hospital. Stroke is the second most common cause of death and disability worldwide, but its molecular mechanisms remain poorly understood, making the development of new treatments a challenge. This study provides a broad and novel perspective on the biological mechanisms that lead to stroke.Stroke can be caused by vascular alterations, including large and small arteries, clots formed in heart cavities and alterations in the venous system. The researchers found genetic risk factors involved in each of these mechanisms. They showed that some genetic risk factors influence specific mechanisms and others affect susceptibility to stroke in general. They also found genetic influences shared between stroke caused by vessel occlusion (the most common cause of stroke, ischemic stroke) and stroke caused by blood vessel rupture (haemorrhagic stroke, the most catastrophic cause of stroke), when they were often thought to have opposite mechanisms. When the researchers took a closer look at the genomic areas identified in the study, "they noted that several of them overlap with genomic areas known to be involved in related vascular conditions such as atrial fibrillation, coronary artery disease, venous thrombosis or some vascular risk factors, especially high blood pressure, and to a lesser extent, hyperlipidemia," commented Dr. Jordi Jiménez Conde of the Neurovascular research group of the Instituto Hospital del Mar de Investigaciones Médicas (IMIM) and neurologist of the Hospital del Mar. By adding data on gene expression, protein expression, and other characteristics in multiple types of cells and tissues, the researchers got the first clues about the specific genes, molecular pathways, and types of cells and tissues through which new genetic risk factors cause a stroke.In addition, the researchers found that "the genes they identified may improve drug targets for antithrombotic therapy, which is used to reopen occluded blood vessels in stroke patients during the acute phase or to prevent vascular events, including stroke. These findings illustrate the potential of genetics for drug discovery. In fact, drugs are already being tested experimentally that modulate a protein encoded in one of these genes and that is an epigenetic regulator," said Dr. Fernandez, researcher in the Neurovascular Diseases group of VHIR and Fundación Docencia e Investigación Mútua Terrassa. "These genetic findings also represent a first step towards the development of personalized treatments based on evidence for this complex disease. They provide knowledge of new biological pathways involved in stroke that can lead to the discovery of new drug targets," explained Dr. Jordi Jiménez Conde."These findings, which relate stroke to multiple other pathologies and to the deregulation of genes, proteins and molecular pathways in specific cell types and organs, were generated through new bioinformatics approaches that use and combine information from various international biological databases, which is of great value, especially when tissue samples from patients are not available," commented Dr. Caty Carrera, researcher in the Neurovascular Diseases group at VHIR. The study was conducted by members of the MEGASTROKE Consortium, which include research groups of strokes from Germany, France, the United Kingdom, Japan, USA, Iceland, Spain, Switzerland, Italy, Belgium, the Netherlands, Denmark, Sweden, Norway, Finland, Estonia and Poland, Singapore, Australia and Canada. This large-scale international collaboration was facilitated by the International Stroke Genetics Consortium, which has brought together stroke genetics experts from around the world for the past 10 years.