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

Bjornsdottir, Gyda; Chalmer, Mona A.; Stefánsdóttir, Lilja; Skuladottir, Astros Th; Einarsson, Gudmundur; Andrésdóttir, Margrét; Beyter, Doruk; Ferkingstad, Egil; Gretarsdottir, Solveig; Halldórsson, Bjarni Vilhjálmur; Halldórsson, Gísli Hreinn; Helgadottir, Anna; Helgason, Hannes; Hjorleifsson Eldjarn, Grimur; Jonasdottir, Adalbjorg; Jonasdottir, Aslaug; Jónsdóttir, Ingileif; Knowlton, Kirk U.; Nadauld, Lincoln D.; Lund, Sigrún Helga; Magnusson, Olafur Th; Melsted, Páll; Moore, Kristjan H.S.; Oddsson, Asmundur; Olason, Pall I.; Sigurdsson, Asgeir; Stefansson, Olafur A.; Saemundsdottir, Jona; Sveinbjornsson, Gardar; Tragante, Vinicius; Unnsteinsdottir, Unnur; Walters, Guðmundur 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; 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; Þorsteinsdóttir, Unnur; Olesen, Jes; Ludvigsson, Petur; Thorarensen, Ólafur; Bjornsdottir, Anna; Sigurdardottir, Gudrun R.; Sveinsson, Ólafur Árni; Ostrowski, Sisse R.; Holm, Hilma; Gudbjartsson, Daniel F.; Thorleifsson, Gudmar; Sulem, Patrick; Stefansson, Hreinn; Thorgeirsson, Thorgeir E.; Hansen, Thomas F.; Stefánsson, Kári

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

Titill:	Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura
Höfundur:	Bjornsdottir, Gyda orcid.org/0000-0002-8100-0306 Chalmer, Mona A. Stefánsdóttir, Lilja Skuladottir, Astros Th Einarsson, Gudmundur Andrésdóttir, Margrét Beyter, Doruk orcid.org/0000-0002-3644-5760 Ferkingstad, Egil orcid.org/0000-0001-8090-7988 Gretarsdottir, Solveig Halldórsson, Bjarni Vilhjálmur ... 84 fleiri höfundar Sýna alla höfunda Halldórsson, Gísli Hreinn Helgadottir, Anna orcid.org/0000-0002-1806-2467 Helgason, Hannes Hjorleifsson Eldjarn, Grimur Jonasdottir, Adalbjorg Jonasdottir, Aslaug Jónsdóttir, Ingileif Knowlton, Kirk U. Nadauld, Lincoln D. Lund, Sigrún Helga orcid.org/0000-0002-3806-2296 Magnusson, Olafur Th Melsted, Páll orcid.org/0000-0002-8418-6724 Moore, Kristjan H.S. Oddsson, Asmundur orcid.org/0000-0002-4606-5163 Olason, Pall I. Sigurdsson, Asgeir Stefansson, Olafur A. Saemundsdottir, Jona Sveinbjornsson, Gardar orcid.org/0000-0003-2429-9468 Tragante, Vinicius Unnsteinsdottir, Unnur Walters, Guðmundur 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 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 Þorsteinsdóttir, Unnur Olesen, Jes Ludvigsson, Petur Thorarensen, Ólafur Bjornsdottir, Anna Sigurdardottir, Gudrun R. Sveinsson, Ólafur Árni Ostrowski, Sisse R. Holm, Hilma orcid.org/0000-0002-9517-6636 Gudbjartsson, Daniel F. Thorleifsson, Gudmar orcid.org/0000-0003-4623-9087 Sulem, Patrick orcid.org/0000-0001-7123-6123 Stefansson, Hreinn orcid.org/0000-0002-9331-6666 Thorgeirsson, Thorgeir E. Hansen, Thomas F. Stefánsson, Kári 94 höfundar Sýna færri höfunda
Útgáfa:	2023-11
Tungumál:	Enska
Umfang:	11
Háskóli/Stofnun:	Landspitali - The National University Hospital of Iceland Reykjavik University
Svið:	Health Sciences
Deild:	Faculty of Industrial Engineering, Mechanical Engineering and Computer Science Faculty of Medicine Faculty of Physical Sciences
Birtist í:	Nature Genetics; 55(11)
ISSN:	1061-4036
DOI:	10.1038/s41588-023-01538-0
Efnisorð:	Barnalæknisfræði; Taugasjúkdómafræði; Humans; Genome-Wide Association Study; Migraine Disorders/genetics; Migraine with Aura/genetics; Phenotype; Epilepsy; Genetics
URI:	https://hdl.handle.net/20.500.11815/4539
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Tilvitnun: Bjornsdottir , G , Chalmer , M A , Stefánsdóttir , L , Skuladottir , A T , Einarsson , G , Andrésdóttir , M , Beyter , D , Ferkingstad , E , Gretarsdottir , S , Halldórsson , B V , Halldórsson , G H , Helgadottir , A , Helgason , H , Hjorleifsson Eldjarn , G , Jonasdottir , A , Jonasdottir , A , Jónsdóttir , I , Knowlton , K U , Nadauld , L D , Lund , S H , Magnusson , O T , Melsted , P , Moore , K H S , Oddsson , A , Olason , P I , Sigurdsson , A , Stefansson , O A , Saemundsdottir , J , Sveinbjornsson , G , Tragante , V , Unnsteinsdottir , U , Walters , G B , Zink , F , Rødevand , L , Andreassen , O A , Igland , J , Lie , R T , Haavik , J , Banasik , K , Brunak , S , Didriksen , M , T. Bruun , M , Erikstrup , C , Kogelman , L J A , Nielsen , K R , Sørensen , E , Pedersen , O B , Ullum , H , Bay , J , Boldsen , J K , Brodersen , T , Burgdorf , K , Dinh , K M , Dowsett , J , Feenstra , B , Geller , F , Hindhede , L , Hjalgrim , H , Jacobsen , R L , Jemec , G , Kaspersen , K , Kjerulf , B D , Larsen , M A H , Louloudis , I , Lundgaard , A , Mikkelsen , S , Mikkelsen , C , Nissen , I , Nyegaard , M , Henriksen , A P , Rohde , P D , Rostgaard , K , Swinn , M , Thørner , L W , Bruun , M T , Werge , T , Westergaard , D , Masson , G , Þorsteinsdóttir , U , Olesen , J , Ludvigsson , P , Thorarensen , Ó , Bjornsdottir , A , Sigurdardottir , G R , Sveinsson , Ó Á , Ostrowski , S R , Holm , H , Gudbjartsson , D F , Thorleifsson , G , Sulem , P , Stefansson , H , Thorgeirsson , T E , Hansen , T F & Stefánsson , K 2023 , ' Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura ' , Nature Genetics , vol. 55 , no. 11 , pp. 1843-1853 . https://doi.org/10.1038/s41588-023-01538-0
Útdráttur: 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.
Athugasemdir: Publisher Copyright: © 2023, The Author(s).