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Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

By Heidi Hautakangas, Bendik S Winsvold, Sanni E Ruotsalainen, Gyda Bjornsdottir, Aster V.E. Harder, Lisette J.A. Kogelman, Laurent F. Thomas, Raymond Noordam, Christian Benner, Padhraig Gormley, Ville Artto, Karina Banasik, Anna Bjornsdottir, Dorret I Boomsma, Ben M Brumpton, Kristoffer Sølvsten Burgdorf, Julie E Buring, Mona Ameri Chalmer, Irene de Boer, Martin Dichgans, Christian Erikstrup, Markus Färkkilä, Maiken Elvestad Garbrielsen, Mohsen Ghanbari, Knut Hagen, Paavo Häppölä, Jouke Jan Hottenga, Maria G. Hrafnsdottir, Kristian Hveem, Marianne Bakke Johnsen, Mika Kähönen, Espen S. Kristoffersen, Tobias Kurth, Terho Lehtimaki, Lannie Lighart, Sigurdur H Magnusson, Rainer Malik, Ole Birger Pedersen, Nadine Pelzer, Brenda WJH Penninx, Caroline Ran, Paul M Ridker, Frits R Rosendaal, Gudrun R. Sigurdardottir, Anne Heidi Skogholt, Olafur A. Sveinsson, Thorgeir E. Thorgeirsson, Henrik Ullum, Lisanne S Vijfhuizen, Elisabeth Widén, Ko Willems van Dijk, International Headache Genetics Consortium, HUNT All-in Headache, Danish Blood Donor Study Genomic Cohort, Arpo Aromaa, Andrea Carmine Belin, Tobias Freilinger, M. Arfan Ikram, Marjo-Riitta Järvelin, Olli Raitakari, Gisela M Terwindt, Mikko Kallela, Maija Wessman, Jes Olesen, Daniel I. Chasman, Dale R Nyholt, Hreinn Stefánsson, Kari Stefansson, Arn M.J.M. van den Maagdenberg, Thomas Folkmann Hansen, Samuli Ripatti, John-Anker Zwart, Aarno Palotie, Matti Pirinen

Posted 25 Jan 2021
medRxiv DOI: 10.1101/2021.01.20.21249647

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. This genome-wide association study (GWAS) of 102,084 migraine cases and 771,257 controls identified 123 loci of which 86 are novel. The loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. A stratification of the risk loci using 29,679 cases with subtype information, of which approximately half have never been used in a GWAS before, indicated three risk variants that appear specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that appear 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.

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