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

Heidi Hautakangas(University of Helsinki), Bendik S. Winsvold(Oslo University Hospital), Sanni Ruotsalainen(University of Helsinki), Gyða Björnsdóttir(deCODE Genetics (Iceland)), Aster V. E. Harder(Leiden University Medical Center), Lisette J. A. Kogelman(Copenhagen University Hospital), Laurent F. Thomas(Norwegian University of Science and Technology), Raymond Noordam(Leiden University Medical Center), Christian Benner(University of Helsinki), Padhraig Gormley(GlaxoSmithKline (United States)), Ville Artto(Helsinki University Hospital), Karina Banasik(Novo Nordisk Foundation), Anna Bjornsdottir, Dorret I. Boomsma(Vrije Universiteit Amsterdam), Ben Brumpton(Norwegian University of Science and Technology), Kristoffer Sølvsten Burgdorf(Copenhagen University Hospital), Julie E. Buring(Brigham and Women's Hospital), Mona Ameri Chalmer(Copenhagen University Hospital), Irene de Boer(Leiden University Medical Center), Martin Dichgans(LMU Klinikum), Christian Erikstrup(Aarhus University Hospital), Markus Färkkilä(Helsinki University Hospital), Maiken Elvestad Garbrielsen(Norwegian University of Science and Technology), Mohsen Ghanbari(Erasmus MC), Knut Hagen(Norwegian University of Science and Technology), Paavo Häppölä(University of Helsinki), Jouke‐Jan Hottenga(Vrije Universiteit Amsterdam), Maria Gudlaug Hrafnsdottir(Reykjavík University), Kristian Hveem(Norwegian University of Science and Technology), Marianne Bakke Johnsen(Oslo University Hospital), Mika Kähönen(Tampere University Hospital), Espen Saxhaug Kristoffersen(Oslo University Hospital), Tobias Kurth(Charité - Universitätsmedizin Berlin), Terho Lehtimäki(Tampere University), Lannie Lighart(Vrije Universiteit Amsterdam), Sigurður H. Magnússon(deCODE Genetics (Iceland)), Rainer Malik(LMU Klinikum), Ole Birger Pedersen(Zealand University Hospital Køge), Nadine Pelzer(Leiden University Medical Center), Brenda W.J.H. Penninx(GGZ inGeest), Caroline Ran(Karolinska Institutet), Paul M. Ridker(Brigham and Women's Hospital), Frits R. Rosendaal(Leiden University Medical Center), Gudrun R. Sigurdardottir, Anne Heidi Skogholt(Norwegian University of Science and Technology), Ólafur Sveinsson(Reykjavík University), Thorgeir E. Thorgeirsson(deCODE Genetics (Iceland)), Henrik Ullum(Copenhagen University Hospital), Lisanne S. Vijfhuizen(Leiden University Medical Center), Elisabeth Widén(University of Helsinki), Ko Willems van Dijk(Leiden University Medical Center), Irene de Boer(Leiden University Medical Center), Arn M. J. M. van den Maagdenberg(Leiden University Medical Center), HUNT All-in Headache(Finnish Institute for Health and Welfare), Danish Blood Donor Study Genomic Cohort(Karolinska Institutet), Arpo Aromaa(Finnish Institute for Health and Welfare), Andrea Carmine Belin(Erasmus MC), Tobias Freilinger(Oulu University Hospital), M. Arfan Ikram(University of Turku), Marjo‐Riitta Järvelin(Oulu University Hospital), Olli T. Raitakari(University of Turku), Gisela M. Terwindt(Leiden University Medical Center), Mikko Kallela(Helsinki University Hospital), Maija Wessman(Brigham and Women's Hospital), Jes Olesen(Queensland University of Technology), Daniel I. Chasman(Brigham and Women's Hospital), Dale R. Nyholt(deCODE Genetics (Iceland)), Hreinn Stefánsson(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland)), Arn M. J. M. van den Maagdenberg(Broad Institute), Thomas Folkmann Hansen(Oslo University Hospital), Samuli Ripatti(Broad Institute), John‐Anker Zwart(Oslo University Hospital), Aarno Palotie(Broad Institute), Matti Pirinen(University of Helsinki)
Nature Genetics
February 1, 2022
10.1038/s41588-021-00990-0
Cited by 388Open Access
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Abstract

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. 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. 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. 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. 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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