GENOME-WIDE ANALYSIS OF 102,084 MIGRAINE CASES IDENTIFIES 123 RISK LOCI AND SUBTYPE-SPECIFIC RISK ALLELES 161 8 Introduction 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 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 three times more prevalent in females than in males. For about one-third of patients, migraine attacks often include an aura phase4 characterized by transient neurological symptoms such as scintillations. Hence, the two main migraine subtypes are defined as migraine with aura (MA) and migraine without aura (MO). It has been debated for decades whether or not the migraine subtypes are in fact two separate disorders,5-7 and if so, what the underlying causes are. Prevailing theories about migraine pathophysiology emphasize neuronal and/or vascular dysfunction.8, 9 Current knowledge on disease mechanisms largely comes from studies of a rare monogenic sub-form of MA, familial hemiplegic migraine, for which three ion transporter genes (CACNA1A, ATP1A2 and SCN1A) have been identified.10 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 The largest GWAS thus far, with 59,674 cases and 316,078 controls, reported 38 genomic loci that confer migraine risk.13 Subsequent analyses of these GWAS data showed enrichment of migraine signals near activating histone marks specific to cardiovascular and central nervous system tissues,14 as well as for genes expressed in vascular and smooth muscle tissues.13 Other smaller GWAS15-21 have suggested 10 additional loci. Of note, the previous datasets were too small to perform a meaningful comparison of the genetic background between migraine subtypes. As migraine is globally the second largest contributor to years lived with disability,2, 3 there is clearly a large need for new treatments. Triptans, i.e., serotonin 5-HT1B/1D receptor agonists, are migraine-specific acute treatments for the headache phase but are not effective in every patient, whereas preventive medication is far from satisfactory alltogether.22 Recent promising alternatives for acute treatment are serotonin 5-HT1F receptor agonists (‘ditans’) 23 and small-molecule calcitonin-gene related peptide (CGRP) receptor antagonists (‘gepants’).24, 25 For preventive treatment, monoclonal antibodies (mAbs) targeting CGRP or its receptor have recently proven effective,26 and new gepants are under development for migraine prevention.27 Still, there remains an urgent need for treatment options for patients who do not respond to the existing treatments. Genetics has proven a promising way to develop novel therapeutic hypotheses in other prevalent complex diseases, such as cardiovascular disease28 and type 2 diabetes,29 and we anticipate that large genetic studies of migraine could also yield similar insights. We conducted a GWAS meta-analysis of migraine by adding to the previous meta-analysis13 42,410 new migraine cases from four study collections (Table 1). This increased the number of migraine cases by 71% for a total sample of 102,084 cases and 771,257 controls. Furthermore,
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