Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Abstract

In the original publication of this paper, the middle initial of Michael D. Ferrari's name was inadvertently left out. This has since been corrected online. The authors apologize for the error.

Two‐pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26

“…In support of these reports, the overexpression of K2P18 in small TRG fibres inhibits action potential firing (Guo and Cao, ), presumably through K2P18‐mediated currents. A growing body of evidence suggests that many cases of migraine are polygenic in nature (Anttila et al, ; Gormley et al, ), leading to the notion that genetic variants in KCNK18 might act as risk factors, rather than as a single, penetrant ‘channelopathy’. However, the notion that activators of K2P18 channels could act as anti‐migraine medications is intriguing and worthy of further investigation.…”

Common Grounds for Family Maladies

“…Rare variants cause Mendelian family aggregation in subsets of common diseases, and common variants may contribute to rare diseases. In this issue of Neuron, Gormley et al (2018) report that the common variant burden in familial migraine is larger than in migraine of the general population.…”

“…Similarly to BrS, the search for rare variants with strong effect on migraine had much less success than expected. Therefore, Gormley et al (2018) performed a polygenic risk score (PRS) analysis based on the migraine GWAS data and determined the PRS levels in a large collection of familial migraine cases. PRS analysis detects the common polygenic burden, since GWAS has little sensitivity in case of rare variants.…”

“…Indeed, for familial hemiplegic migraine, the authors found that 45% of the families carried a common variant burden that was in the highest quartile of the PRS distribution, while only 9% carried a pathogenic mutation in one of the three known FHM genes. Gormley et al (2018) based their migraine PRS analysis on GWAS data recalculated after exclusion of the Finnish subset and then compared the PRS levels in Finnish population cases versus Finnish family cases. This might raise concerns, since the variant distribution in the Finnish population deviates from non-Finnish Europeans.…”

“…This deviation, caused by a population bottleneck in Finnish history, is large only for rare variants, however, while for common variants as included in the PRS analysis the difference is marginal (Chheda et al, 2017). Moreover, Gormley et al (2018) tested the PRS method for bias by deriving PRS instruments from international GWAS on other traits (i.e., IQ and schizophrenia) and determining the corresponding PRS levels in Finnish migraine cases. Neither the population cases nor the family cases displayed any enrichment in that test, confirming the validity of the method.…”