Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura
Year: 2023
Type: article
Study design: Observational Study
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.
Source: Nature Genetics
Authors: Gyda Bjornsdottir, Mona A. Chalmer, Lilja Stefansdottir, Astros Th. Skuladottir, Gudmundur Einarsson, Margret Andresdottir, Doruk Beyter, Egil Ferkingstad, Solveig Gretarsdottir, Bjarni V. Halldorsson, Gisli H. Halldorsson, Anna Helgadottir, Hannes Helgason, Grimur Hjorleifsson Eldjarn, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Ingileif Jonsdottir, Kirk U. Knowlton, Lincoln D. Nadauld, Sigrun H. Lund, Olafur Th. Magnusson, Pall Melsted, Kristjan H. S. Moore, Asmundur Oddsson, Pall I. Olason, Asgeir Sigurdsson, Olafur A. Stefansson, Jona Saemundsdottir, Gardar Sveinbjornsson, Vinicius Tragante, Unnur Unnsteinsdottir, G. Bragi Walters, Florian Zink, Linn Rødevand, Ole A. Andreassen, Jannicke Igland, Rolv T. Lie, Jan Haavik, Karina Banasik, Søren Brunak, Maria Didriksen, Mie T. Bruun, Christian Erikstrup, Lisette J. A. Kogelman, Kaspar R. Nielsen, Erik Sørensen, Ole B. Pedersen, Henrik Ullum, Jakob Bay, Jens K. Boldsen, Thorsten Brodersen, Kristoffer Burgdorf, Khoa M. Dinh, Joseph Dowsett, Bjarke Feenstra, Frank Geller, Lotte Hindhede, Henrik Hjalgrim, Rikke L. Jacobsen, Gregor Jemec, Katrine Kaspersen, Bertram D. Kjerulf, Margit A. H. Larsen, Ioannis Louloudis, Agnete Lundgaard, Susan Mikkelsen, Christina Mikkelsen, Ioanna Nissen, Mette Nyegaard, Alexander P. Henriksen, Palle D. Rohde, Klaus Rostgaard, Michael Swinn, Lise W. Thørner, Mie T. Bruun, Thomas Werge, David Westergaard, Gisli Masson, Unnur Thorsteinsdottir, Jes Olesen, Petur Ludvigsson, Olafur Thorarensen, Anna Bjornsdottir, Gudrun R. Sigurdardottir, Olafur A. Sveinsson, Sisse R. Ostrowski, Hilma Holm, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Patrick Sulem, Hreinn Stefansson, Thorgeir E. Thorgeirsson, Thomas F. Hansen, Kari Stefansson
Institutions: deCODE Genetics (Iceland), Copenhagen University Hospital, Rigshospitalet, Reykjavík University, University of Iceland, Intermountain Healthcare, Oslo University Hospital, University of Oslo, Western Norway University of Applied Sciences, University of Bergen, Norwegian Institute of Public Health, Haukeland University Hospital, University of Copenhagen, Novo Nordisk Foundation, Odense University Hospital, Aarhus University, Aarhus University Hospital, Aalborg University Hospital, Aalborg University, Zealand University Hospital Køge, Statens Serum Institut, Danish Cancer Society, Zealand University Hospital, Sankt Hans Hospital, National University Hospital of Iceland
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Funders: Van Andel Research Institute, University of Miami, University of Pennsylvania, Harvard University, North Carolina State University, Broad Institute, Leidos, European Commission, Novo Nordisk, Université de Genève, Novo Nordisk Fonden, National Institutes of Health, Horizon 2020 Framework Programme, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
Awards: Methods for high-resolution analysis of genetic effects on gene expression, G1076064052, G1217436835, G138129434, G143460415, G1534570039, G1561323845, G1650773652, G1883398070, G2003871768, G2040478069, G2158443041, G2204307168, G2568082621, G2651523388, G275953476, G2835668146, G2877753951, G292137090, G3002430358, G3221727586, G32319252, G3387558946, G3443372292, G347407575, G3503792436, G3547560438, G3722710735, G3793778294, G386607036, G3952396931, G4110903388, G4124418613, G4282887365, Molecular Mechanisms Associating Chronic Pain with Fatigue, Affective Disorders, Cardiovascular Disease and Total Comorbidity, G4382062407, G4478373029, G4510456360, G4715193760, G4729234894, G4770637985, G4937468798, G5096786130, G563538711, G5737582129, G5888954722, G6317516893, G6678493692, G7274654584, G7353525908, G7468954878, G7665525972, G7761642487, G7953026188, G8494855175, G8719970897, G8788848806, G8858395165, G8906494432, G9000036744, G9000103821, G9000118502, G9000173623, G9000221753, G9000288902
OpenAlex ID: W4387955535