8 CHAPTER 8 162 we assessed the subtype specificity of the risk loci in 8,292 new MA and 6,707 new MO cases in addition to the 6,332 MA and 8,348 MO cases used previously13 (Table 2). Here we report 123 genomic loci, of which 86 are novel, and include the first four loci that reach genome-wide significance (P < 5 × 10-8) in MA. Our subtype data compellingly show that migraine risk is conferred both by risk loci that appear specific for only one subtype as well as by loci that are shared by both subtypes. Our findings also include new risk loci containing target genes of recent migraine drugs acting on the CGRP pathway and the serotonin 5-HT1F receptor. Finally, our data support the concept that migraine is brought about by both neuronal and vascular genetic factors, strengthening the view that migraine truly is a neurovascular disorder. Methods Cohorts and phenotyping All participating studies were approved by local research ethics committees, and written informed consent was obtained from all study participants. For all the participating studies, an approval was received to use the data in the present work. Study-specific ethics statements are provided in the Supplementary Note. First, we performed a genome-wide meta-analysis on migraine including five study collections listed in Table 1 and Supplementary Table 1. Second, we performed subtype-specific metaanalyses on MA and on MO, both including five study collections listed in Table 2, for the 123 independent risk variants identified in the migraine analysis. A description of the study collections is given in the Supplementary Note. In particular, the migraine phenotype has been self-reported in other cohorts except in IHGC2016, where a subset of patients were phenotyped in specialized headache centers, as previously explained.13 Table 1 Five migraine study collections included in the meta-analysis Abbreviation Full name Ancestry Cases Controls Case % Migraine definition IHGC2016* Gormley et al. 2016 (no 23andMe) European descent 29,209 172,931 14.4 Self-reported and ICHD-II 23andMe** 23andMe, Inc. (23andMe.com) European descent 53,109 230,876 18.7 Self-reported UKBB UK Biobank (ukbiobank.ac.uk) European, British 10,881 330,170 3.2 Self-reported GeneRISK GeneRISK (generisk.fi) European, Finnish 1,084 4,857 18.2 Self-reported HUNT Nord-Trøndelag Health Study (ntnu. edu/hunt) European, Norwegian 7,801 32,423 19.4 Self-reported migraine or fulfilling modified ICHD-II criteria *IHGC2016 is a meta-analysis of 21 studies listed in Supplementary Table 1 and does not include data from 23andMe. Some studies of IHGC2016 determined migraine status through clinical phenotyping, while migraine status in other studies is based on self-reported information. **23andMe includes 30,465 cases from Gormley et al. (2016) metaanalysis and 22,644 new cases. ICHD-II, the International Classification of Headache Disorders 2nd edition.
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