FINAL REPORT: Whole Exome Sequencing as a Strategy for Gene Discovery in a Large Well Characterized Family with Migraine (2011)

Summary

We received funding from the Migraine Research Foundation to identify genes underlying the migraine phenotype from a multigenerational, deeply migraine penetrant family. MRF also funded the initial DNA sampling effort that has become the Migraine Genomic Library from which the probands were drawn (see below).

From the Migraine Genomic Library, we identified probands in large families affected with migraine. In those families we are carrying out Whole Exome Sequencing (WES) to discover migraine causative genes. Thus far we have studied two large families and found likely cause genetic variants in both. The first family was characterized by early onset, pure migraine with aura (MA) in all affected blood line members and a pattern of inheritance suggestive of autosomal dominant. We found 5 candidate variants were present in all of the affected family members and none of the non-affected family members. The second family had a larger pedigree and more varied phenotype with members having both MA and migraine without aura (MO). In this family, we identified a variant gene which segregated with both MA and MO but not with non-affected family members.  When we analyzed the members in family 2 who had a Mendelian pattern of inheritance and MA, comparing them to the non-affected family members, we found additional variants that segregated with MA.

One particularly interesting finding was that all subjects with MA studied in the two completely unrelated families showed alteration in genes whose protein product binds to a regulatory gene whose protein product in turn binds to and affects genes that have been linked to a strong MA phenotype. It also regulates several genes involved in one of the prominent mechanisms of action of Topiramate, an effective antimigraine prophylactic drug.

Hypothesis vs. Findings

Our results have confirmed the hypothesis that Whole Exome Sequencing can yield causative candidate gene variants within two well phenotyped families. Additional families must be studied to confirm or refute the variants found.

Unanswered Questions

Migraine has a complex pathophysiology that unfolds through a cascade of events that leads to two major phenotypic events:

1. the transient brain dysfunction that underlies the migraine aura; and
2. the repeated non-adaptive activations of the trigeminocervical pain system that results in the migrainous headache.

Variation in the genes either regulating or directly involved in any modulating process in the migraine cascade may increase or decrease migraine risk in an individual. Our goal is to discover as many causative variants and the genes they alter to identify the common pathophysiological signaling mechanisms and/or perturbed molecular pathways underlying the two major migraine phenotypic events. Our findings suggest the possibility that one set of variants may confer susceptibility to aura, while others render the affected individuals susceptible to migrainous headache attacks. We intend to continue this line of inquiry in additional families to confirm or refute our preliminary findings.

In the investigation of migraine pathophysiology, common variants are no more informative than rare or uncommon variants. We propose to emphasize the discovery of rare and uncommon variants by WES as a much more cost effective strategy to achieve an understanding of the biological underpinnings of migraine because each informative family potentially provides an important piece in the puzzle of migraine pathophysiology. The strategy to emphasize discovery of common variants has proven to be very expensive and of limited yield.

What This Research Means to You

We ultimately seek to use the identified molecular mechanisms to drive a new therapeutic approach that moves prophylactic treatment away from inefficient, empiric therapy and toward treatment that addresses the underlying molecular cause(s) of migraine in each individual patient.

FINAL REPORT: Investigation of the Genetic Basis of Migraine: Building a DNA Library in Migraine Sufferers (2008)

Published in Open Journal of Genetics, Volume 3, Number 2A3, August 2013

Summary

We proposed to establish a DNA library with samples from well characterized migraine sufferers and unrelated age/gender matched controls whose detailed clinical and diagnostic phenotype is carefully gathered and recorded in a searchable electronic database.  The first use of the library will be to carry out the first whole genome association study of migraine in a well characterized American population. Our project was not a specific study but rather the development of a DNA library that will serve as a resource for migraine research in the coming decades.

We have accomplished our goal in no small part due to the generosity of the Migraine Research Foundation.  We have established what is probably the largest migraine specific DNA repository in the world. In the 12 months that we have received MRF support, we have sampled over 1,400 migraine case and non-migraine controls subjects, bringing the total samples to 2,316. Of those we have sampled 737 Migraine without aura subjects (MWO), 716 Migraine with aura (MWA) subjects and 863 non-Migraine controls (NMC) subjects. Later this year, we will begin the application process for funding of the first migraine specific genome-wide association study of Migraine in the US. Because of the increasingly competitive environment especially as it pertains to NIH funding, we are increasing the number of sampled subjects that we will include in our proposal as we go forward. Our goal is to have sampled 4500 subjects for the GWAS (1500 MWO, 1500 MWA, 1500 NMC). We have acquired funding which will hopefully carry us to the completion of this goal. Our work is on-going and progressing well.

Hypothesis vs. Findings

Our hypotheses that establishment of such a repository was feasible and that we would have the capability to sample the large number of subjects required to carry out this research have been validated.

Unanswered Questions

It is our hope and expectation that the library will form the basis of the first Genome Wide Association Study (GWAS) in the United States. We will also use this repository to carry out migraine genetics research projects with a more limited scope as we continue to recruit and sample subjects for the GWAS. Two genetics projects are underway:

• We are currently genotyping subjects to assess the association of migraine with Serotonin receptor 2A and 2C and Serotonin transport gene polymorphisms.
• We are in the midst of developing a project to assess the genotype-phenotype correlation between candidate gene polymorphisms and menstrually-associated migraine.

In addition, we have begun to glean clinical data from the computerized repository of clinical phenotypic information to which the DNA genotypic data will be correlated.

What this Research Means to You

For the first time, we showed that the association with migraine of several genes involved in the hormones underlying the menstrual cycle relate to the variant form of the gene in women whose migraine attacks are worse or more frequent around the time of their menstrual flow. This is the first time that a gene variant has been shown to correlate with a specific clinical characteristic of patients with one of the common forms of migraine. It is an exciting result that may point to a future in which treatment of a patient with migraine is based on the actual genetically-based biological cause of their migraine.

Learn More

F. Michael Cutrer, MD, is conducting ground-breaking research in migraine genetics by building a unique DNA library of migraine sufferers at the Mayo Clinic that he hopes will change the way doctors diagnose and treat migraine. The Migraine Research Foundation helped Dr. Cutrer get his work off the ground with a grant for his project “Investigation of the Genetic Basis of Migraine: Building a DNA Library in Migraine Sufferers.”

Dr. Cutrer’s current research involves compiling an extensive library of DNA from migraine sufferers, which includes a detailed patient history and information about each sufferer’s condition. He explains that migraine is thought to be influenced by a number of genes, making it difficult to determine its genetic basis. By identifying which genes are associated with different types of migraine, doctors will be able to better diagnose migraine patients and prescribe treatments that are more likely to work for each patient.

With support from MRF, Dr. Cutrer was able to move his work forward and greatly increase the number of DNA samples in the library. In the future, he hopes to collaborate with research centers across the country to gather data from more diverse patient groups, providing an even better picture of the genetic basis for migraine.

Dr. Cutrer has been able to combine an interest in research with a personal desire for a cure, as he has suffered from migraine since he was a teenager. But he did not always plan to focus on migraine research. He is a talented musician and earned degrees in music while also studying his other passion, science. Though he did consider pursuing a career in music, Dr. Cutrer ultimately opted for a more stable life in medicine. As a medical student, Dr. Cutrer was fascinated by the complexity of the nervous system and was drawn to neurology because it is a field where “not all the answers are known.” Although he planned to specialize in epilepsy, he decided instead to focus on migraine during his residency. He realized that the migraine sufferers who made up a large number of his clinic patients were not improving. Drawn to the challenge of the migraine puzzle and motivated by his own suffering, Dr. Cutrer decided to devote his career to migraine research.

Dr. Cutrer thinks this is an exciting time for migraine research because advances in medical technology have begun to allow researchers to find answers to their questions. He remains driven both by his passion for science and his personal connection to migraine, as now two of his children also suffer. He advises young researchers in all fields to pick an area of focus in which they have a personal connection or an intellectual curiosity.