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

2023; Nature Portfolio; Volume: 55; Issue: 11 Linguagem: Inglês

10.1038/s41588-023-01538-0

1546-1718

Gyða Björnsdóttir, Mona Ameri Chalmer, Lilja Stefánsdóttir, Ástrós Th. Skúladóttir, Guðmundur Einarsson, Margrét B. Andrésdóttir, Doruk Beyter, Egil Ferkingstad, Sólveig Grétarsdóttir, Bjarni V. Halldórsson, Gísli H. Halldórsson, Anna Helgadóttir, Hannes Helgason, Grímur Hjörleifsson Eldjárn, Aðalbjörg Jónasdóttir, Áslaug Jónasdóttir, Ingileif Jónsdóttir, Kirk U. Knowlton, Lincoln Nadauld, Sigrún H. Lund, Ólafur Þ. Magnússon, Páll Melsted, Kristjan H. S. Moore, Ásmundur Oddsson, Pall I. Olason, Ásgeir Sigurðsson, Ólafur Andri Stefánsson, Jona Saemundsdottir, Garðar Sveinbjörnsson, Vinicius Tragante, Unnur Unnsteinsdóttir, G. Bragi Walters, Florian Zink, Linn Rødevand, Ole A. Andreassen, Jannicke Igland, Rolv T. Lie, Jan Haavik, Karina Banasik, Søren Brunak, Maria Didriksen, Mie Topholm Bruun, Christian Erikstrup, Lisette J. A. Kogelman, Kaspar René Nielsen, Erik Sørensen, Ole Birger Pedersen, Henrik Ullum, Jakob Thaning Bay, Jens Kjærgaard Boldsen, Thorsten Brodersen, Kristoffer Sølvsten Burgdorf, Khoa Manh Dinh, Joseph Dowsett, Bjarke Feenstra, Frank Geller, Lotte Hindhede, Henrik Hjalgrim, Rikke Louise Jacobsen, Gregor B. E. Jemec, Kathrine Agergård Kaspersen, Bertram D. Kjerulf, Margit Anita Hørup Larsen, Ioannis Louloudis, Agnete Troen Lundgaard, Susan Mikkelsen, Christina Mikkelsen, Janna Nissen, Mette Nyegaard, Alexander Pil Henriksen, Palle Duun Rohde, Klaus Rostgaard, Michael Swinn, Lise Wegner Thørner, Mie Topholm Bruun, Thomas Werge, David Westergaard, Gísli Másson, Unnur Þorsteinsdóttir, Jes Olesen, Pétur Lúðvígsson, Ólafur Thorarensen, Anna Bjornsdottir, Gudrun R. Sigurdardottir, Ólafur Sveinsson, Sisse Rye Ostrowski, Hilma Hólm, Daníel F. Guðbjartsson, Guðmar Þorleifsson, Patrick Sulem, Hreinn Stefánsson, Thorgeir E. Thorgeirsson, Thomas Hansen, Kári Stéfansson,

Thyroid Disorders and Treatments

Abstract 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.