Largest genome-wide association study of migraine to date

Performing a meta-analysis with over 100,000 migraine cases, researchers from Finland identified 123 risk loci for migraine, of which 86 were new. Among the new risk loci were genes that are targeted by recently developed migraine therapeutics (monoclonal antibodies, gepants, and ditans) [1].

Based on family and twin studies, the heritability of migraine has been estimated to be ~42% [2]. Previous genome-wide association studies (GWAS) have reported approximately 48 risk loci. The largest study was published in 2016, identifying 38 risk loci for migraine when comparing almost 60,000 cases with over 300,000 controls [3]. That study showed enrichment in genes highly expressed in vascular and smooth muscle tissue.

Researchers from Finland conducted the largest GWAS of migraine to date and further evaluated shared and distinct genetic components in the 2 main migraine subtypes: with and without aura [1]. Included were 102,084 migraine cases and ~771,000 controls. Ms Heidi M. Hautakangas (Institute for Molecular Medicine, Finland) shared the results.

The researchers identified 123 risk loci, of which 86 were newly identified. When stratifying the risk loci by subtypes, they indicated:

• 3 risk variants that appeared specific for migraine with aura (in HMOX2, CACNA1A, and MPPED2);
• 2 risk variants that appeared specific for migraine without aura (near SPINK2 and near FECH); and
• 9 risk variants that increased susceptibility for migraine regardless of subtype.

Two of the newly identified risk loci were related to targets of new migraine treatments, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F).

Furthermore, the researchers reported enrichment of migraine signal in 5 cell types from the central nervous system, 3 cardiovascular cell types, and in single-cell types of the digestive system, musculoskeletal/connective tissue, and ovary. In addition, they identified risk alleles that appeared specific for migraine with or without aura, and risk alleles that were shared by both subtypes.

The observed genomic annotations among migraine-associated variants support the hypothesis that neurovascular mechanisms underlie the pathophysiology of migraine. Currently, the Finnish researchers prepare for colocalisation analyses as well as fine-mapping of the risk loci to narrow down potential causal variants and genes driving the association signals.

1. Hautakangas HM, et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. AL04, IHC 2021, 8–12 September.
2. Polderman TJ, et al. Nat Genet. 2015;47(7):702–9.
3. Gormley P, et al. Nat Genet. 2016;48(8):856–66.

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Posted on 8 November 2021