Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Abstract Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. This genome-wide association study (GWAS) of 102,084 migraine cases and 771,257 controls identified 123 loci of which 86 are novel. The loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. A stratification of the risk loci using 29,679 cases with subtype information, of which approximately half have never been used in a GWAS before, indicated three risk variants that appear specific for migraine with aura (in HMOX2, CACNA1A and MPPED2 ), two that appear specific for migraine without aura (near SPINK2 and near FECH ), and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide ( CALCA/CALCB ) and serotonin 1F receptor ( HTR1F ). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.