학술논문
Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura
Document Type
Article
Author
Bjornsdottir, Gyda; Chalmer, Mona A.; Stefansdottir, Lilja; Skuladottir, Astros Th.; Einarsson, Gudmundur; Andresdottir, Margret; Beyter, Doruk; Ferkingstad, Egil; Gretarsdottir, Solveig; Halldorsson, Bjarni V.; Halldorsson, Gisli H.; Helgadottir, Anna; Helgason, Hannes; Hjorleifsson Eldjarn, Grimur; Jonasdottir, Adalbjorg; Jonasdottir, Aslaug; Jonsdottir, Ingileif; Knowlton, Kirk U.; Nadauld, Lincoln D.; Lund, Sigrun H.; Magnusson, Olafur Th.; Melsted, Pall; Moore, Kristjan H. S.; Oddsson, Asmundur; Olason, Pall I.; Sigurdsson, Asgeir; Stefansson, Olafur A.; Saemundsdottir, Jona; Sveinbjornsson, Gardar; Tragante, Vinicius; Unnsteinsdottir, Unnur; Walters, G. 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; Masson, Gisli; Thorsteinsdottir, Unnur; Olesen, Jes; Ludvigsson, Petur; Thorarensen, Olafur; Bjornsdottir, Anna; Sigurdardottir, Gudrun R.; Sveinsson, Olafur A.; Ostrowski, Sisse R.; Holm, Hilma; Gudbjartsson, Daniel F.; Thorleifsson, Gudmar; Sulem, Patrick; Stefansson, Hreinn; Thorgeirsson, Thorgeir E.; Hansen, Thomas F.; Stefansson, Kari
Source
Nature Genetics; 20230101, Issue: Preprints p1-11, 11p
Subject
Language
ISSN
10614036; 15461718
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, ABOand LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2confers 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 KCNK5confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.