Common Genetic Variation Contributes to Migraines in Families

What's the science?

Migraine is an extremely common disorder affecting up to 20% of adults in developed countries. Migraines tend to run in families, however, the genetic risk underlying this is not well understood. A typical way to study genetic risk is to look at rare genetic mutations, which often put a person at high risk for a disease disease. However, ‘common’ genetic variations (i.e. single nucleotide polymorphisms) in the population could have a significant contribution to risk of migraine that runs in families. This week in Neuron, Gormley and colleagues test whether a genetic risk score (of common genetic variants) is associated with migraines that aggregate in families.

How did they do it?

They used a dataset including 1589 families (a total of 8319 family members) with genotype information. They generated a polygenic risk score for each individual using a set of SNPs (single nucleotide polymorphisms; commonly occurring changes in the genetic code), that were previously shown to be associated with migraine risk. They tested for the association between this polygenic risk score and risk of different migraine subtypes including migraine with aura, migraine without aura and a rare form of migraine (hemiplegic migraine) in families (using ‘logistic mixed modelling’ which controlled for sex, age and genetic relatedness) compared to a large group of controls. They also compared the risk of migraine explained by the genetic risk score in families to a large sample population of unrelated individuals with migraine.  

What did they find?

They found that the genotypes associated with risk for migraine (from the polygenic risk score) were enriched (i.e. more common) in families with all forms of migraine compared to controls. The strongest association was for the migraine with aura, followed by hemiplegic migraine and migraine without aura. In particular, a subtype of migraine hemiplegic migraine had the strongest enrichment of polygenic risk. Polygenic risk score explained 3.5% of the variance in families (for presence of migraine) compared to 1.6% variance explained (for presence of migraine) in the general population. When compared to people with migraine in the general population, family members with migraine showed a greater burden of polygenic risk (more risk variants in their genome) and this was strongest for hemiplegic migraine followed by migraine with typical aura and migraine without aura. Furthermore, in a genetic transmission test they found that in families, offspring with migraine received a higher percentage of common migraine risk variants from their parents then would be expected by chance, suggesting that these common genetic risk variants are over-transmitted to family members with migraine.

What's the impact?

This is the first study to show that common genetic variation known to associate with migraine risk, is enriched (more common) in families compared to those with migraines in the general population. Before this study, the contributions of common genetic variants to migraine risk in families was unclear. We now know that common genetic risk variants that contribute to all forms of migraine risk are transmitted through families.

Gormley et al., Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1589 Families. Neuron (2018). Access the original scientific publication here.