Journal Article

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

Belin, Andrea Carmine, Kogelman, Lisette J. A., Pirinen, Matti, Skogholt, Anne Heidi, Olesen, Jes, Burgdorf, Kristoffer Sølvsten, Noordam, Raymond, Färkkilä, Markus, Magnusson, Sigurdur H., Pedersen, Ole Birger, Winsvold, Bendik S., van Dijk, Ko Willems, Hveem, Kristian, Järvelin, Marjo-Riitta, Stefansson, Kari, Hottenga, Jouke-Jan, Kallela, Mikko, Ikram, M. Arfan, Johnsen, Marianne Bakke, Freilinger, Tobias, Boomsma, Dorret I., Penninx, Brenda W. J. H., Lehtimäki, Terho, Kristoffersen, Espen S., Häppölä, Paavo, Sveinsson, Olafur A., Terwindt, Gisela M., Stefánsson, Hreinn, Hautakangas, Heidi, Benner, Christian, de Boer, Irene, Gormley, Padhraig, Hagen, Knut, Bjornsdottir, Gyda, Ghanbari, Mohsen, Kähönen, Mika, Chalmer, Mona Ameri, Erikstrup, Christian, Wessman, Maija, Sigurdardottir, Gudrun R., Vijfhuizen, Lisanne S., Nyholt, Dale R., Garbrielsen, Maiken Elvestad, Thorgeirsson, Thorgeir E., Raitakari, Olli T., Brumpton, Ben M., Lighart, Lannie, Ullum, Henrik, Ran, Caroline, Thomas, Laurent F., Buring, Julie E., Aromaa, Arpo, Banasik, Karina, Chasman, Daniel I., Zwart, John-Anker, Ripatti, Sam

2022

Overview

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. Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/43 / 631/208/205/2138 / 692/699/375/1654 / Agriculture / Alleles / Animal Genetics and Genomics / Annotations / Biomedical and Life Sciences / Biomedicine / Calcitonin / Calcitonin gene-related peptide / Cancer Research / Cardiovascular System - metabolism / Case-Control Studies / Central nervous system / Central Nervous System - metabolism / Gene Function / Gene loci / Genetic Loci / Genetic Predisposition to Disease / Genome-wide association studies / Genome-Wide Association Study / Genomes / Headache / Human Genetics / Humans / Meta-analysis / Migraine / Migraine Disorders - genetics / Migraine with Aura - genetics / Molecular Sequence Annotation / Nervous system / Nervous tissues / Pathophysiology / Peptides / Polymorphism, Single Nucleotide / Proteins / Quantitative Trait Loci / Risk / Serotonin / Therapeutic targets