Many migraines may have a common genetic basis
A study into the genetic basis of many common forms of migraine has identified three variants that suggest that most forms of migraine have a shared genetic foundation, regardless of how they manifest in the people who have them.
Migraine affects up to 20 per cent of the population and is defined as being ‘with aura’ (where the migraine is preceded by symptoms such as visual disturbances, slurred speech or numbness), or ‘without aura’ where the migraine starts without any warning.
Although migraine has an inheritable component, until recently the only genetic variants associated with the condition were for rare forms of the condition where just one gene had altered – known as ‘rare variants’.
Little is known about the genetic basis of more common forms of migraine that are believed to be due to many factors, including variants that affect a number of chemical processes in brain. In September 2010, genome wide association studies revealed the first common variant associated with migraine and showed it was associated with a chemical communication system in nerves in the brain known as the glutamate signalling pathway. This current study has applied a similar approach to identify more areas of the genome that may have an effect on common forms of migraine.
The research team compared the genomes of more than 8,000 people who have migraines with 37,000 individuals who are migraine-free. To achieve this scale, the study combined data from two large migraine research initiatives, the US-based Women’s Genome Health Study and the European-based International Headache Genetics Consortium with two smaller studies from the Netherlands and Germany.
By conducting a genome-wide association study (GWAS), the researchers were able to zoom in on variants that could increase susceptibility to migraine. The study found three genetic variants that were equally associated with migraines with aura and migraines without aura.
“Most forms of migraine are likely to be due to a number of affected pathways working in concert. This study has found three areas of the human genome that are associated with migraine at the population level that are shared by people who have attacks with aura and without aura. It offers the possibility that migraines may be due to disturbances in signalling pathways that are common to all forms of the condition. Our work will stimulate more targeted research to unveil more precise mechanisms of these genes.”
Dr Tobias Kurth Senior author of the study from INSERM, France as well as Brigham and Women’s Hospital, Harvard Medical School, Boston
Two of the variants identified by the study are clearly associated with migraines only – affecting the genes LRP1 and TRPM8, with the variant affecting TRPM8 appearing to be more prevalent in women. In contrast the third variant that affects the gene PRDM16 appears to have a function in both migraines and non-migraine headaches, but the pathway it affects is unknown. The targets of these variants both confirm current thinking on the causes of migraine and shed new light on a mechanism not previously linked to the condition.
“By associating a variant that affects the gene LRP1 with common migraines, this confirms that the glutamate signalling pathway is involved in the development of migraines. This agrees with our previous study where we identified the first variant associated with common migraine, which also affected the glutamate signalling pathway. The second variant appears to affect the gene TRPM8, which is expressed in neurons and encodes a sensor for pain.
“The third variant has yet to be linked to any particular signalling pathway and elucidating its role should provide further knowledge of why people experience the symptoms they do with migraines.”
Professor Aarno Palotie Senior Group Leader at the Wellcome Trust Sanger Institute and one of the authors of the study
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Funding
For a full list of agencies that supported this work, please see the Nature Genetics website.
Participating Centres
For a full list of participating centres that supported this work, please see the Nature Genetics website.
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INSERM
Founded in 1964, the French National Institute of Health and Medical Research (Inserm) is a public scientific and technological institute which operates under the joint authority of the French Ministry of Health and French Ministry of Research. As the only French public research institute to focus entirely on human health, in 2008 Inserm took on the responsibility for the strategic, scientific and operational coordination of biomedical research. This key role as coordinator comes naturally to Inserm thanks to the scientific quality of its teams and its ability to conduct translational research, from the laboratory to the patient’s bed.
Brigham and Women's Hospital
Brigham and Women’s Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is the home of the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), www.brighamandwomens.org/research, BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $537 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses’ and Physicians’ Health Studies and the Women’s Health Initiative.
The Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.
The Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.
