The largest genome-wide association study (GWAS) thus far, with 59,674 cases and 316,078 controls, reported 38 genomic loci that confer migraine risk 13. The common forms of migraine (MA and MO) instead have a complex polygenic architecture with an increased familial relative risk 5, increased concordance in monozygotic twins 11 and a heritability of 40–60% 12. Current knowledge of disease mechanisms comes largely from studies of a rare monogenic subform of MA-familial hemiplegic migraine-for which three ion transporter genes ( CACNA1A, ATP1A2 and SCN1A) have been identified 10. Prevailing theories about migraine pathophysiology emphasize neuronal and/or vascular dysfunction 8, 9. It has been debated for decades whether or not the migraine subtypes are in fact two separate disorders 5, 6, 7, and, if so, what the underlying causes are. Hence, the two main migraine subtypes are defined as migraine with aura (MA) and migraine without aura (MO). For about one-third of patients, migraine attacks often include an aura phase 4 characterized by transient neurological symptoms such as scintillations. Migraine is three times more prevalent in females than in males. Migraine has a lifetime prevalence of 15–20% and is ranked as the second most disabling condition in terms of years lived with disability 2, 3. Migraine is a highly prevalent brain disorder characterized by disabling attacks of moderate-to-severe pulsating and usually one-sided headache that may be aggravated by physical activity, and can be associated with symptoms such as a hypersensitivity to light and sound, nausea and vomiting 1. 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. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide ( CALCA/CALCB) and serotonin 1F receptor ( HTR1F). 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. 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. 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. Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Nature Genetics volume 54, pages 152–160 ( 2022) Cite this article Danish Blood Donor Study Genomic Cohort,.International Headache Genetics Consortium,. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
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