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. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem 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.

NCOR2 is a novel candidate gene for migraine-epilepsy phenotype

“…One of the 123 migraine risk loci recently reported by the International Headache Genetics Consortium (24) co-localizes with the linked region segregating in the studied family. From these 123 independent loci, 86 were reported for the first time while 37 loci overlapped with the previously reported 48 loci.…”

“…Migraine-epilepsy risk locus shows the position of the shared haplotype on 12q24.31 (chr12:124,832,606-125,283,766; GRCh37) identified in this study. Migraine risk locus was identified in the recent, and so far the largest, genome-wide analysis on migraine (102,084 cases and 77,1257 controls) (24). The risk locus (chr12:124,806,051-124,826,676; GRCh37) covers a 20.6 kbp large region having eight variants in high LD (r2 > 0.6) with the lead variant rs1271309 ( p -value 3.74 × 10 −8 ) while the genomic area showing genome-wide significant or suggestive association with migraine ( p -value <1 × 10 −5 ) covers a 377 kbp large region on chr12:124,642,694–125,019,242 (GRCh37) (24).…”

“…The 12q24.31 linkage locus was further studied utilizing the largest migraine GWAS meta-analysis dataset of 102,084 affected subjects and 771,257 controls (24). In this study, altogether 10,843,197 markers were tested using the inverse-variance weighted fixed-effects meta-analysis approach.…”

“…In this study, altogether 10,843,197 markers were tested using the inverse-variance weighted fixed-effects meta-analysis approach. The procedure of the GWAS meta-analysis and the data collections are described in detail in the original publication (24).…”

“…We compared the location of the migraine risk locus at 12q24.31 showing evidence of genome-wide significant and suggestive ( p -value <1 × 10 −5 ) association with migraine (24) with the haplotype shared by the studied family. We also determined genotypes of the proband IV:29 (mother with epilepsy and migraine) for the migraine GWAS risk variants.…”