The minor effects of multiple genetic variants may determine migraine risk

A transatlantic team studied a dataset of more than 1,500 families in Finland to investigate two competing theories about how migraines run in families. To their surprise, they discovered that the collective effects of many genetic variants drive migraine risk more than a few powerful genes do—a revelation that might uncover new pathways for therapies. 

The so-called powerful genes come under a Mendelian inheritance model, where a child inherits one copy of the gene from each parent, and this inherited combination determines a trait or disease. Previous work has pinpointed a trio of genes, ACNA1A, ATP1A2 and SCN1A, that are linked to hemiplegic migraine, a form of migraine that causes stroke-like symptoms. 

The other approach is called polygenic inheritance. Polygenic traits, such as a person's height, are determined by genes that, individually, have minor effects, but combine to influence the trait or risk of disease. 

To test the two scenarios in the Finnish dataset, the team created a polygenic risk score using data from a genome-wide study that identified chromosome locations, or "loci," that differed between people with the same disease. The genomewide association study included data from about 59,000 migraine cases and 316,000 control cases and was led by scientists from the Broad Institute of MIT and Harvard. 

They calculated the polygenic risk score for the 8,319 people in the family migraine study, as well as the score for more than 14,400 people in the FINRISK population survey. The family study included data across migraine type, including hemiplegic migraine and migraine without aura, while the FINRISK study included data on 1,101 people with migraine. 

The scientists found that common polygenic variants "significantly contribute" to migraine risk, regardless of migraine type. The findings appeared (PDF) in the journal Neuron. 

"If a person's migraines started at an earlier age, if a person experienced more severe migraines, or if migraines ran in a person's family, the data showed that it's more likely that person had a greater genetic burden of common polygenic variants to blame," they wrote in a statement. 

As for the three powerful Mendelian genes, they turned out to play a relatively minor role. The researchers sequenced the genes of 45 families found to have hemiplegic migraine in the family study. Of the 45, they found only four families whose disease was driven by the Menelian genes. The other cases were influenced by polygenic variants. 

The research may open up new avenues for a field with no cure and in which current treatments include repurposed epilepsy, depression, or high blood pressure drugs to prevent attacks. Several companies, including Allergan, Novartis, Eli Lilly and Teva are racing to bring a new class of migraine drug to market. They target the neurotransmitter calcitonin gene-related peptide (CGRP) with the goal of warding off a migraine attack. The majority of CGRP-targeting monoclonal antibodies are intravenous therapies, but Allergan and Biohaven are working on oral versions.

The revelations from the Finnish families could point drug researchers in entirely new directions.

"This really shows, in a very big sample set, that common variants are very important factors in aggregation of migraines in the family," said Aarno Palotie, of the Institute for Molecular Medicine in Finland and the Broad Institute.

Palotie thinks more sequencing and larger studies will turn up further migraine-linked variants, both polygenic and Mendelian. Then, scientists could investigate how these variants affect migraine-related pathways and develop new drugs to target them. 

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