Common, Rare Variants Impact Genetic Migraine Risk

Aarno Palotie, MD, PhD

The largest genetic family study to be conducted on migraine has found a calculable personal genetic risk score that was applicable to approximately 60,000 patients.

Researchers from the University of Helsinki, Helsinki University Central Hospital, the Broad Institute of MIT and Harvard, analyzed the medical and genetic history of 1589 Finnish migraine families that includes 8300-plus individuals.

As one of the most common brain disorders in the world, migraine has a propensity to affect families at an abnormal rate. However, the molecular mechanisms of the condition that lead to genetic clustering are still a relative mystery to clinicians.

This most recent study also pulled from the analysis of more than 59,000 total migraine patients by the research team, which had already led to the identification of 40-plus significant genetic risk variants that place individuals at risk of migraines. Previous work has also indicated this number may be small: hundreds, maybe even thousands, of supplemental variants may have minute impacts on individual migraine risk.

Researchers used this information to calculate the genetic risk score, estimating and comparing the genetic burden driven by commonly-shard variants in different migraine patient subgroups.

Study first author Padhraig Gormley, PhD, from Broad Institute of MIT and Harvard, said their intent was to give weight to each of these variants.

“Both rare, high-impact and common genetic variants with smaller impact could contribute to the familial aggregation of migraine,” Gormley said. “In this study, we wanted to find out which one is more important and whether the genetic load is higher in certain types of migraine.”

The family migraine cohort study reported 2420 patients as having diagnoses of migraine with typical aura, and another 540 with hemiplegic aura symptoms. Aura is a supplemental neurological symptom that occurs during migraine attacks in approximately one-third of all patients.

The contribution of both common and rare genetic variation to hemiplegic migraine — a condition previously attributed to rare pathogenic variants in 3 different genes — surprised researchers, as the genetic load was highest in this patient subgroup among all populations.

Researchers also found an overall increased genetic risk score in family-based migraine cases, versus that of general migraine cases from another large Finnish population sample of 15,000 participants (1100 with migraine). This comparison also showed clear differences of the common variant load across different migraine subtypes.

Genetic risk score was also associated the age of onset of migraine headaches, researchers wrote. Genetic load was notably higher in patient cases where headache onset occurred before 20 years of age, compared to individuals who reported later onset.

The cohort study concluded with support of the hypothesis that migraine subtypes are genetically heterogeneous diseases, Aarno Palotie, MD, PhD, of the Institute for Molecular Medicine Finland, University of Helsinkim, said. It also found that polygenic variation is a significant contributor to the aggregation of both common and rare migraine subtypes in families.

“We were surprised by the impact of the common variants in these families. However, much of the genetic predisposition to migraine still remains unexplained,” Palotie said. “It is likely that further studies will reveal more common and rare migraine risk variants."

The study was published online in the journal Neuron Thursday morning.

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