Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

• Published in: Nature genetics Vol. 55; no. 11; pp. 1843 - 1853
• Main Authors: Bjornsdottir, Gyda, Chalmer, Mona A., Stefansdottir, Lilja, Skuladottir, Astros Th, Einarsson, Gudmundur, Andresdottir, Margret, Beyter, Doruk, Ferkingstad, Egil, Gretarsdottir, Solveig, Halldorsson, Bjarni V., Halldorsson, Gisli H., Helgadottir, Anna, Helgason, Hannes, Hjorleifsson Eldjarn, Grimur, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Jonsdottir, Ingileif, Knowlton, Kirk U., Nadauld, Lincoln D., Lund, Sigrun H., Magnusson, Olafur Th, Melsted, Pall, Moore, Kristjan H. S., Oddsson, Asmundur, Olason, Pall I., Sigurdsson, Asgeir, Stefansson, Olafur A., Saemundsdottir, Jona, Sveinbjornsson, Gardar, Tragante, Vinicius, Unnsteinsdottir, Unnur, Walters, G. Bragi, Zink, Florian, Rødevand, Linn, Andreassen, Ole A., Igland, Jannicke, Lie, Rolv T., Haavik, Jan, Banasik, Karina, Brunak, Søren, Didriksen, Maria, T. Bruun, Mie, Erikstrup, Christian, Kogelman, Lisette J. A., Nielsen, Kaspar R., Sørensen, Erik, Pedersen, Ole B., Ullum, Henrik, Masson, Gisli, Thorsteinsdottir, Unnur, Olesen, Jes, Ludvigsson, Petur, Thorarensen, Olafur, Bjornsdottir, Anna, Sigurdardottir, Gudrun R., Sveinsson, Olafur A., Ostrowski, Sisse R., Holm, Hilma, Gudbjartsson, Daniel F., Thorleifsson, Gudmar, Sulem, Patrick, Stefansson, Hreinn, Thorgeirsson, Thorgeir E., Hansen, Thomas F., Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/79; 38/91; 45; 45/43; 631/208/205/2138; 631/378; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Brain; Cancer Research; Datasets; Epilepsy; Gene Function; Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Headache; Headaches; Human Genetics; Humans; LRRK2 protein; Migraine; Migraine Disorders - genetics; Migraine with Aura - genetics; Pain perception; Phenotype; Phenotypes; Population studies; Potassium channels; Sensation; Signs and symptoms; Denmark; United Kingdom > UK; United States > US; Norway; Iceland; Finland
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-023-01538-0

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2 , PALMD , ABO and LRRK2 ) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A , encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis -regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes. Genome-wide association analyses of migraine and its subtypes identify new susceptibility loci, including rare variants with large effects implicating PRRT2 , SCN11A and KCNK5 .