Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura
-
Published:2023-10-26
Issue:11
Volume:55
Page:1843-1853
-
ISSN:1061-4036
-
Container-title:Nature Genetics
-
language:en
-
Short-container-title:Nat Genet
Author:
Bjornsdottir GydaORCID, Chalmer Mona A.ORCID, Stefansdottir Lilja, Skuladottir Astros Th.ORCID, Einarsson GudmundurORCID, Andresdottir Margret, Beyter Doruk, Ferkingstad EgilORCID, Gretarsdottir SolveigORCID, Halldorsson Bjarni V.ORCID, Halldorsson Gisli H.ORCID, Helgadottir AnnaORCID, Helgason Hannes, Hjorleifsson Eldjarn GrimurORCID, Jonasdottir Adalbjorg, Jonasdottir Aslaug, Jonsdottir IngileifORCID, Knowlton Kirk U., Nadauld Lincoln D., Lund Sigrun H.ORCID, Magnusson Olafur Th., Melsted Pall, Moore Kristjan H. S.ORCID, Oddsson AsmundurORCID, Olason Pall I., Sigurdsson Asgeir, Stefansson Olafur A.ORCID, Saemundsdottir Jona, Sveinbjornsson GardarORCID, Tragante ViniciusORCID, Unnsteinsdottir Unnur, Walters G. BragiORCID, Zink Florian, Rødevand Linn, Andreassen Ole A.ORCID, Igland Jannicke, Lie Rolv T.ORCID, Haavik JanORCID, Banasik KarinaORCID, Brunak SørenORCID, Didriksen MariaORCID, T. Bruun MieORCID, Erikstrup ChristianORCID, Kogelman Lisette J. A.ORCID, Nielsen Kaspar R., Sørensen Erik, Pedersen Ole B.ORCID, Ullum Henrik, Bay Jakob, Boldsen Jens K., Brodersen Thorsten, Burgdorf Kristoffer, Dinh Khoa M., Dowsett Joseph, Feenstra Bjarke, Geller Frank, Hindhede Lotte, Hjalgrim Henrik, Jacobsen Rikke L., Jemec Gregor, Kaspersen Katrine, Kjerulf Bertram D., Larsen Margit A. H., Louloudis Ioannis, Lundgaard Agnete, Mikkelsen Susan, Mikkelsen Christina, Nissen Ioanna, Nyegaard Mette, Henriksen Alexander P., Rohde Palle D., Rostgaard Klaus, Swinn Michael, Thørner Lise W., Bruun Mie T., Werge Thomas, Westergaard David, Masson Gisli, Thorsteinsdottir Unnur, Olesen JesORCID, Ludvigsson Petur, Thorarensen Olafur, Bjornsdottir Anna, Sigurdardottir Gudrun R., Sveinsson Olafur A., Ostrowski Sisse R.ORCID, Holm HilmaORCID, Gudbjartsson Daniel F.ORCID, Thorleifsson GudmarORCID, Sulem PatrickORCID, Stefansson Hreinn, Thorgeirsson Thorgeir E., Hansen Thomas F.ORCID, Stefansson KariORCID,
Abstract
AbstractMigraine 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.
Publisher
Springer Science and Business Media LLC
Reference98 articles.
1. Lipton, R. B. & Bigal, M. E. The epidemiology of migraine. Am. J. Med. 118, 3S–10S (2005). 2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38, 1–211 (2018). 3. Rasmussen, B. K. & Olesen, J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 12, 221–228 (1992). 4. Lauritzen, M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 117, 199–210 (1994). 5. Lai, J. & Dilli, E. Migraine aura: updates in pathophysiology and management. Curr. Neurol. Neurosci. Rep. 20, 17 (2020).
|
|