Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura
Gyða Björnsdóttir(deCODE Genetics (Iceland)), Mona Ameri Chalmer(Copenhagen University Hospital), Lilja Stefánsdóttir(deCODE Genetics (Iceland)), Ástrós Skúladóttir(deCODE Genetics (Iceland)), Guðmundur Einarsson(deCODE Genetics (Iceland)), Margrét B. Andrésdóttir(deCODE Genetics (Iceland)), Doruk Beyter(deCODE Genetics (Iceland)), Egil Ferkingstad(deCODE Genetics (Iceland)), Sólveig Grétarsdóttir(deCODE Genetics (Iceland)), Bjarni V. Halldórsson(Reykjavík University), Gísli H. Halldórsson(deCODE Genetics (Iceland)), Anna Helgadóttir(deCODE Genetics (Iceland)), Hannes Helgason(deCODE Genetics (Iceland)), Grímur Hjörleifsson Eldjárn(deCODE Genetics (Iceland)), Aðalbjörg Jónasdóttir(deCODE Genetics (Iceland)), Áslaug Jónasdóttir(deCODE Genetics (Iceland)), Ingileif Jónsdóttir(deCODE Genetics (Iceland)), Kirk U. Knowlton(Intermountain Medical Center), Lincoln Nadauld(Intermountain Healthcare), Sigrún H. Lund(deCODE Genetics (Iceland)), Ólafur Þ. Magnússon(deCODE Genetics (Iceland)), Páll Melsted(deCODE Genetics (Iceland)), Kristjan H. S. Moore(deCODE Genetics (Iceland)), Ásmundur Oddsson(deCODE Genetics (Iceland)), Pall I. Olason(deCODE Genetics (Iceland)), Ásgeir Sigurðsson(deCODE Genetics (Iceland)), Ólafur Andri Stefánsson(deCODE Genetics (Iceland)), Jona Saemundsdottir(deCODE Genetics (Iceland)), Garðar Sveinbjörnsson(deCODE Genetics (Iceland)), Vinicius Tragante(deCODE Genetics (Iceland)), Unnur Unnsteinsdóttir(deCODE Genetics (Iceland)), G. Bragi Walters(deCODE Genetics (Iceland)), Florian Zink(deCODE Genetics (Iceland)), Linn Rødevand(Oslo University Hospital), Ole A. Andreassen(Oslo University Hospital), Jannicke Igland(Western Norway University of Applied Sciences), Rolv T. Lie(Norwegian Institute of Public Health), Jan Haavik(Haukeland University Hospital), Karina Banasik(University of Copenhagen), Søren Brunak(University of Copenhagen), Maria Didriksen(Copenhagen University Hospital), Mie Topholm Bruun(Odense University Hospital), Christian Erikstrup(Aarhus University), Lisette J. A. Kogelman(Copenhagen University Hospital), Kaspar René Nielsen(Aalborg University Hospital), Erik Sørensen(Copenhagen University Hospital), Ole Birger Pedersen(University of Copenhagen), Henrik Ullum(Statens Serum Institut), Jakob Thaning Bay(Zealand University Hospital Køge), Jens Kjærgaard Boldsen(Aarhus University Hospital), Thorsten Brodersen(Zealand University Hospital Køge), Kristoffer Sølvsten Burgdorf(University of Copenhagen), Khoa Manh Dinh(Aarhus University Hospital), Joseph Dowsett(Copenhagen University Hospital), Bjarke Feenstra(Statens Serum Institut), Frank Geller(Statens Serum Institut), Lotte Hindhede(Aarhus University Hospital), Henrik Hjalgrim(Danish Cancer Society), Rikke Louise Jacobsen(Copenhagen University Hospital), Gregor B. E. Jemec(Zealand University Hospital), Katrine Kaspersen(Aarhus University Hospital), Bertram D. Kjerulf(Aarhus University Hospital), Margit Anita Hørup Larsen(Copenhagen University Hospital), Ioannis Louloudis(University of Copenhagen), Agnete Troen Lundgaard(University of Copenhagen), Susan Mikkelsen(Aarhus University Hospital), Christina Mikkelsen(Copenhagen University Hospital), Janna Nissen(Copenhagen University Hospital), Mette Nyegaard(Aalborg University), Alexander Pil Henriksen(University of Copenhagen), Palle Duun Rohde(Aalborg University), Klaus Rostgaard(Danish Cancer Society), Michael Swinn(Copenhagen University Hospital), Lise Wegner Thørner(Copenhagen University Hospital), Mie Topholm Bruun(Odense University Hospital), Thomas Werge(University of Copenhagen), David Westergaard(University of Copenhagen), Gísli Másson(deCODE Genetics (Iceland)), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Jes Olesen(Copenhagen University Hospital), Pétur Lúðvígsson(National University Hospital of Iceland), Ólafur Thorarensen(National University Hospital of Iceland), Anna Bjornsdottir, Gudrun R. Sigurdardottir, Ólafur Sveinsson(Reykjavík University), Sisse Rye Ostrowski(University of Copenhagen), Hilma Hólm(deCODE Genetics (Iceland)), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Patrick Sulem(deCODE Genetics (Iceland)), Hreinn Stefánsson(deCODE Genetics (Iceland)), Thorgeir E. Thorgeirsson(deCODE Genetics (Iceland)), Thomas Folkmann Hansen(University of Copenhagen), Kāri Stefánsson(deCODE Genetics (Iceland))
Cited by 54Open Access
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.
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