Seventeen genetic abnormalities that cause brain aneurysms

December 07, 2020

Nearly three percent of the world's population is at risk of developing an intracranial aneurysm, a localized dilation of a blood vessel forming a fragile pocket. Rupture of this aneurysm results in extremely severe, and, in one-third of cases, fatal haemorrhage. In the framework of the International Stroke Genetics Consortium, a team led by the University of Geneva (UNIGE), the University Hospitals of Geneva (HUG) and the University of Utrecht is studying the genetic determinants of aneurysms in order to better understand the different forms of the disease and to assess individual risk. Through the examination of the genome of more than 10,000 people suffering from aneurysms compared to that of 300,000 healthy volunteers, 17 genetic abnormalities have been identified that are notably involved in the functioning of the vascular endothelium, the inner lining of blood vessels. In addition, the scientists discovered a potential link between these genetic markers and anti-epileptic drugs, making it possible to consider the use of certain drugs in the management of the disease. These results, to be read in the journal Nature Genetics, also highlight how the wise use of large databases containing genomic and phenotypic information can advance research.

Every year, five out of every 100,000 people experience a rupture of an intracranial aneurysm - as many as those injured in road accidents. And only very rapid and highly specialized surgical management can hope to save their lives. «It is therefore essential to better understand the genetic basis - inherited or otherwise - governing the risk of developing the disease, but also to distinguish between the different forms of the disease and its severity. This will allow us to detect people at risk and offer them the most appropriate treatment,» explains Philippe Bijlenga, Assistant Professor in the Department of Clinical Neurosciences at UNIGE Faculty of Medicine and Senior Consultant at HUG Division of Neurosurgery, who led the Swiss part of this study. This multipronged disease, whose evolution depends on genetic, congenital and environmental factors, is indeed complex to apprehend. «The tiny variations that make it up must therefore be deciphered,» he adds.

A study of unprecedented scope

The work carried out in Geneva and Utrecht is the largest genetic study in the world in the field of intracranial aneurysms. The DNA of more than 10,000 patients was examined and compared with that of 300,000 volunteers: eleven new regions of the genome - compared with six previously - were found to be associated with the disease. «Each of these DNA variations causes a slight increase in the risk of an intracranial aneurysm,» says Ynte Ruigrok, neurologist and associate professor at the University Medical Center of Utrecht University, who co-led the study. «Thus, their accumulation can, together, constitute a significant risk."

Most of these genetic abnormalities appear to be related to the functioning of the endothelial cells that line the inside of blood vessels and usually make them robust. "These cells have long been suspected of being responsible for aneurysms,» says Philippe Bijlenga. «We now have evidence that leads us to work on possible markers of instability that could indicate whether the aneurysm is stable, healed, or at high risk of adverse outcomes."

In addition, this research shows that a genetic predisposition to high blood pressure and smoking play an important role in the development of an intracranial aneurysm. If these risk factors were already known from a clinical and epidemiological point of view, we now have the genetic evidence.

The scientists also made a surprising discovery: «It appears that the protein structures of some of the genes we identified are linked to antiepileptic drugs. We do not yet know whether this effect is positive or negative, but it opens up the possibility for pharmacological treatments, potentially less invasive than the surgical approaches we are currently using,» says Philippe Bijlenga. The scientists will now work on modelling the disease, both biologically and therapeutically, to offer physicians a medical decision support system that will help determine potential management protocols based on each person's genetic data.

Scientific advances and data protection

To carry out these studies, the research teams must have access to a very large number of patients, and therefore work in international consortia. «To achieve this, we have set up tools to standardize complex data. We had to find a common language, unify clinical evaluation criteria, imaging methods and their computer processing, and establish exchange structures while guaranteeing the protection of personal data,» reports Philippe Bijlenga, who supervised this work on data.

The consortium has set up a structure capable of collecting, harmonizing and securing huge amounts of data. The Swiss Institute of Bioinformatics (SIB) manages the phenotypic data, while the University of Utrecht stores the genomic data. Both datasets are accessible through an approval process to research teams around the world. «However, proper use must be demonstrated. Our system allows scientific advances, but with protection of personal data,» the authors conclude.

Université de Genève

Related Genome Articles from Brightsurf:

Genome evolution goes digital
Dr. Alan Herbert from InsideOutBio describes ground-breaking research in a paper published online by Royal Society Open Science.

Breakthrough in genome visualization
Kadir Dede and Dr. Enno Ohlebusch at Ulm University in Germany have devised a method for constructing pan-genome subgraphs at different granularities without having to wait hours and days on end for the software to process the entire genome.

Sturgeon genome sequenced
Sturgeons lived on earth already 300 million years ago and yet their external appearance seems to have undergone very little change.

A sea monster's genome
The giant squid is an elusive giant, but its secrets are about to be revealed.

Deciphering the walnut genome
New research could provide a major boost to the state's growing $1.6 billion walnut industry by making it easier to breed walnut trees better equipped to combat the soil-borne pathogens that now plague many of California's 4,800 growers.

Illuminating the genome
Development of a new molecular visualisation method, RNA-guided endonuclease -- in situ labelling (RGEN-ISL) for the CRISPR/Cas9-mediated labelling of genomic sequences in nuclei and chromosomes.

A genome under influence
References form the basis of our comprehension of the world: they enable us to measure the height of our children or the efficiency of a drug.

How a virus destabilizes the genome
New insights into how Kaposi's sarcoma-associated herpesvirus (KSHV) induces genome instability and promotes cell proliferation could lead to the development of novel antiviral therapies for KSHV-associated cancers, according to a study published Sept.

Better genome editing
Reich Group researchers develop a more efficient and precise method of in-cell genome editing.

Unlocking the genome
A team led by Prof. Stein Aerts (VIB-KU Leuven) uncovers how access to relevant DNA regions is orchestrated in epithelial cells.

Read More: Genome News and Genome Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to