Genetic causes of migraine discovered

Kiel/Ulm/Oxford/Boston, June 23, 2013. In the most comprehensive migraine study to date, an international consortium of researchers has discovered five new gene regions that are considered to play a role in the development of migraines. The study opens new doors to understanding the causes and biological triggers of migraine attacks. "The newly discovered genes are functionally important for nerve cell signaling, energy metabolism in nerve cells, and memory processing in the brain," says study co-author Prof. Dr. Hartmut Göbel from the Migraine and Headache Center at the Kiel Pain Clinic. "This provides a basis for the targeted development of new treatment methods that can precisely intervene in the mechanisms underlying the development of migraines." The results were published on June 23, 2013, in the renowned journal Nature Genetics.

An international research team identified twelve regions in the genome of migraine patients that contribute to the risk of developing migraines. Eight of these regions were discovered near genes that play a role in controlling brain circuits. Two of these gene regions are responsible for maintaining normal brain and nerve cell function. The regulation of these circuits is considered significant for the genetic risk of developing migraines.

Migraine is a severely disabling disease affecting approximately 14% of the adult population. It has been ranked as the seventh most disabling disease in human history and the most expensive neurological disease. Migraine is difficult to study scientifically because there are currently no clear biomarkers for the period between or during migraine attacks.

“This study has provided new insights into the biological mechanisms of migraine,” says co-author Dr. Aarno Palotie, Wellcome Trust Sanger Institute, University of Oxford, England: “Migraine is a particularly complex neurological disorder and is difficult to analyze in scientific studies; between attacks, the patient is healthy, making it hard to uncover biological changes. We have demonstrated that genetic studies are a very effective way to investigate the biochemical and biological changes in migraine that underlie the core of the disease.”.

The international research team discovered the underlying genetic risk factors by summarizing and comparing the results of over 29 different genome studies. These studies include more than 100,000 patients with migraines and control subjects.

“The new research findings are based, among other things, on carefully diagnosed migraine cases from international migraine centers,” says co-author Prof. Dr. Hartmut Göbel from the Migraine and Headache Center at the Kiel Pain Clinic: “In close collaboration with scientists from the Institute of Human Genetics at the University of Ulm, we analyzed the genetic material of affected families over many years. This international collaboration made it possible to analyze data from 29 studies with a total of 23,285 migraine patients and 95,425 control subjects.”.

The researchers found that some of the risk regions are very close to gene loci that regulate sensitivity to oxidative stress in nerve cells. Oxidative stress is a process that leads to the malfunction of nerve cells.

“A particular challenge will now be to clarify in detail which molecular mechanisms actually underlie this genetic predisposition, because only this knowledge will possibly allow us to develop new and more targeted treatment measures,” explains co-author Dr. Christian Kubisch from the Institute of Human Genetics at the University of Ulm.

The research team assumes that many of the identified risk genes are functionally interconnected and have the potential to disrupt the internal regulation of nerve cells in the brain. This leads to the development of migraine attacks.

“We could not have made this discovery if we had only examined smaller groups of patients and test subjects,” says co-author Dr. Gisela Terwindt from Leiden University, Netherlands: “This large study with over 100,000 samples examined from migraine patients and control subjects allows us to specifically uncover the genetic basis and analyze it further in the laboratory.”.

The team identified an additional 134 gene regions that increase the risk of migraines, but these showed weaker statistical significance. Whether and how these regions interact requires further investigation. Other similar studies have shown that, in total, such gene regions can play an equally significant role in the development of the disease.

“This research methodology is the most efficient way to uncover the biological mechanisms of neurological diseases,” says co-author Dr. Mark Daly of Massachusetts General Hospital and the Broad Institute of MIT, Harvard (USA). “Effective studies that provide us with biological and biochemical insights into the development of such diseases are essential for better understanding and deciphering these severe, debilitating conditions.” Expanding such studies with even more in-depth analysis of biological markers will increase our ability to uncover the causes and triggers of these serious, often lifelong, neurological diseases.