ARTICLE IN BRIEF
An accumulation of common genetic variants, rather than individual variants, elevates the risk for familial migraine, a new study found.
The cumulative burden of many common genetic variants, rather than the inheritance of one or a few specific genes, increases the risk for migraine and causes it to run in families, a large genetics study of families with migraine found.
The study analyzed medical history and genetic data for 1,589 families, comprising 8,139 individuals, in Finland to understand why some families are prone to migraine and what the genetic underpinnings of that susceptibility may be.
The disorder tends to run in families, but until now it has not been clear why that is the case. One theory has been that the familial profile of migraine is due to the passing along of rare, highly penetrant genes, but this new study offers a different explanation.
“The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine,” the research team from Finland and the US reported in the May 16 issue of the journal Neuron.
First author Padhraig Gormley, PhD, a research fellow at Massachusetts General Hospital and the Broad Institute of MIT and Harvard, said the study “shows that in terms of the genetic factors that contribute to migraine, migraine is a very complex disease involving multiple genes.”
While more than 40 genetic variants associated with migraine have been identified, he said there likely are “hundreds, possibly thousands of genetic risk variants for migraine and it all depends on the random shuffle of the deck you get from your parents.”
“Some people in the family get lucky,” he said. “They get a good hand of genetic variants and they don't get the disease. Other family members get a lot of these genetic variants and are at risk for migraine.”
The study has no immediate clinical relevance for the treatment of migraine, he said, but down the road doctors might be able to use a patient's genetic profile to select the optimal medication. A fuller understanding of the genetics, and underlying molecular mechanisms, at work in migraine could lead to the development of new drugs.
STUDY DESIGN, FINDINGS
Researchers at multiple institutions, including the Broad Institute and the Institute for Molecular Medicine Finland at the University of Helsinki, conducted the study.
The researchers said that the identification of three ion-transporter genes (CACNA1A, ATP1A2, SCN1A) linked to a rare type of migraine, hemiplegic migraine, lends support to the “Mendelian viewpoint that segregating, highly penetrating variants contribute to the familial nature of the disease.”
But previous genome-wide association studies by this team and others have identified at least 40 genetic variants associated with migraine, which suggests that familial migraine could be due to the inheritance of multiple genes that individually contribute a small effect but in combination significantly increase the risk for headache.
The family cohort used for this latest study included 540 persons with hemiplegic migraine, 2,430 with migraine with typical aura, 2,357 with migraine without aura, and 3,002 family members with no migraine. Using previous genome-wide association studies data, the researchers generated migraine polygenic risk scores for each of the participants to reflect the degree to which a given person had the common genetic variants associated with migraine.
The results for the family members were then compared to genetic data on healthy controls in non-familial migraine cases, including a population-based sample of 14,470 people (1,101 with migraine) from the so-called FINRISK cohort.
The comparison found that the familial cases of migraine had a “significantly higher common variant burden” than did the migraine cases in the population sample. That held true for all types of migraine, though particularly for migraine with aura subtypes, including hemiplegic migraine. By examining medical records for the family migraine sufferers, the researchers also found that higher risk scores (PRS) were associated with an earlier onset of migraine, before the age of 20, and more symptoms.
The researchers found, on the other hand, a small occurrence of the three known genes for hemiplegic migraine. Those genes were found in only around 10 percent — four of 45 — of cases of familial hemiplegic migraine (FHM).
“While it is possible that more pathogenic, rare variants for FHM are yet to be discovered, it is striking that so few known variants could be identified in our large family collection,” they noted in their report.
The researchers said their findings on the polygenetic nature of familial migraine are “in line with merging evidence from other complex traits, where familial forms of disease that were once thought to be mostly explained by rare variants have been found to also have a strong contribution from common variation.” Other examples include dyslipidemia, Alzheimer's disease, and type 2 diabetes, they said.
The study received partial funding from the drug maker Merck, and the research team included researchers with the DNA-analysis company 23andMe.
William R. Renthal, MD, PhD, director of headache genetics at the Graham Headache Center at Brigham and Women's Hospital, said the study “suggests that the summation of small effects from multiple variants in an individual's genome sequence is driving their risk for migraine.” There may be a “threshold” beyond which the accumulation of genetic variants results in clinical manifestations of migraine, he said.
Dr. Renthal said one of the next challenges is to understand how these migraine-associated variants alter brain function to increase susceptibility to migraine. He is focused on that work in his lab using a technique called single-cell RNA sequencing. He said some migraine-associated genes are expressed primarily in neurons, while others are in vascular cells or glia, so an individual may have distinct mechanisms that cause their susceptibility to migraine depending on which DNA variants they inherit.
“As advances in DNA sequencing technologies improve, genetics will play a much larger role in our diagnostics and treatment...but that isn't tomorrow,” Dr. Renthal said.
Louis J. Ptacek, MD, Distinguished Professor of Neurology at University of California, San Francisco, said he believes that more can be learned sooner about the biology of migraine by studying the known Mendelian genes associated with migraine as opposed to taking the genome-wide approach of sorting through hundreds or thousands of candidate variants that could turn out to have only a limited role or no functional relevance at all.
“The question is how do you get from finding these variants and proving they are causative and understanding what pathways they are affecting?” said Dr. Ptacek, who helped identify a gene connected to familial migraine with aura, called CKIdelta.
“The beauty of Mendelian genetics is that you can prove this is the gene, this is the mutation, and then study the pathways in which the gene and the encoded proteins function. By doing that, you are going to find other genes and proteins in the pathway,” he said.
Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, characterized the new research as a “landmark study,” but said it's only the beginning of understanding migraine, which traditionally was thought of more narrowly as a disease due to brain excitability.
“It is very informative but it is also confounding,” he said. With many genes apparently involved in migraine to varying degrees, “it makes it harder” to figure out which genes would be most effective for targeting in treatment, he said.
“It makes precision medicine more difficult,” said Dr. Shapiro, who is a consultant for Eli Lilly, which has a migraine drug in development. He was also part of the research team that identified the CKIdelta gene
Dr. Shapiro said he believed that a combination of research, focused on both the Mendelian genes and the findings coming from genome-wide association studies, will yield a fuller picture of migraine.
Elizabeth Loder, MD, professor of neurology at Harvard Medical School and chief of the division of headache at Brigham and Women's, said the study points to the complexity of migraine.
“Even though a diagnosis is based on a small number of features, at the genetic level it seems things are quite complicated,” Dr. Loder said. She said a deeper understanding of the genetic, as well as the environmental factors, involved in migraine should help inform both clinical decision-making and new drug development.
“When it comes to daily headache, our treatments are not very good,” she said.
Dr. Loder said currently clinicians often work under the assumption that if a family member responded well to a particular migraine drug, say a triptan, that another family member will have a favorable response to the same drug. That may turn out to be true, but having a rationale for treatment based on a person's genetic profile could lead to the use of an ideal therapy or dosage sooner not later, Dr. Loder said.
She said that given the emerging evidence that migraine is a “highly polygenic, multifactorial disease,” it is unlikely there is ever going “to be one thing that works for everyone.”