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

被引：24

作者：

Bjornsdottir, Gyda ^{[1
]}

Chalmer, Mona A. ^{[2
]}

Stefansdottir, Lilja ^{[1
]}

Skuladottir, Astros Th. ^{[1
]}

Einarsson, Gudmundur ^{[1
]}

Andresdottir, Margret ^{[1
]}

Beyter, Doruk ^{[1
]}

Ferkingstad, Egil ^{[1
]}

Gretarsdottir, Solveig ^{[1
]}

Halldorsson, Bjarni V. ^{[1
,3
]}

Halldorsson, Gisli H. ^{[1
,4
]}

Helgadottir, Anna ^{[1
]}

Helgason, Hannes ^{[1
,4
]}

Eldjarn, Grimur Hjorleifsson ^{[1
]}

Jonasdottir, Adalbjorg ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Jonsdottir, Ingileif ^{[1
,5
]}

Knowlton, Kirk U. ^{[6
]}

Nadauld, Lincoln D. ^{[7
]}

Lund, Sigrun H. ^{[8
]}

Magnusson, Olafur Th. ^{[1
]}

Melsted, Pall ^{[1
]}

Moore, Kristjan H. S. ^{[1
]}

Oddsson, Asmundur ^{[1
]}

Olason, Pall I. ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Stefansson, Olafur A. ^{[1
]}

Saemundsdottir, Jona ^{[1
]}

Sveinbjornsson, Gardar ^{[1
]}

Tragante, Vinicius ^{[1
]}

Unnsteinsdottir, Unnur ^{[1
]}

Walters, G. Bragi ^{[1
]}

Zink, Florian ^{[1
]}

Rodevand, Linn ^{[9
,10
]}

Andreassen, Ole A. ^{[9
,10
]}

Igland, Jannicke ^{[11
,12
]}

Lie, Rolv T. ^{[11
,13
]}

Haavik, Jan ^{[14
,15
]}

Banasik, Karina ^{[16
]}

Brunak, Soren ^{[16
]}

Didriksen, Maria ^{[17
]}

Bruun, Mie T. ^{[18
]}

Erikstrup, Christian ^{[19
,20
]}

Kogelman, Lisette J. A.

Nielsen, Kaspar R. ^{[21
,22
]}

Sorensen, Erik

Pedersen, Ole B. ^{[23
,24
]}

Ullum, Henrik ^{[25
]}

Masson, Gisli ^{[1
]}

Thorsteinsdottir, Unnur ^{[1
]}

机构：

[1] IdeCODE Genet Amgen Inc, Reykjavik, Iceland

[2] Copenhagen Univ Hosp, Dept Neurol, Danish Headache Ctr, Rigshosp Glostrup, Copenhagen, Denmark

[3] Reykjavik Univ, Sch Technol, Reykjavik, Iceland

[4] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[5] Univ Iceland, Sch Hlth Sci, Fac Med, Reykjavik, Iceland

[6] Intermt Heart Inst, Salt Lake City, UT USA

[7] Intermt Healthcare, Saint George, UT USA

[8] Univ Iceland, Sch Engn & Nat Sci, Fac Phys Sci, Reykjavik, Iceland

[9] Oslo Univ Hosp, Div Mental Hlth & Addict, Ctr Mental Disorders Res, NORMENT, Oslo, Norway

[10] Univ Oslo, Inst Clin Med, Oslo, Norway

[11] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway

[12] Western Norway Univ Appl Sci, Ctr Evidence Based Practice, Dept Hlth & Social Sci, Bergen, Norway

[13] Norwegian Inst Publ Hlth, Ctr Fertil & Hlth, Oslo, Norway

[14] Univ Bergen, Dept Biomed, Bergen, Norway

[15] Haukeland Hosp, Div Psychiat, Bergen, Norway

[16] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark

[17] Copenhagen Univ Hosp, Dept Clin Immunol, Rigshosp, Copenhagen, Denmark

[18] Odense Univ Hosp, Dept Clin Immunol, Odense, Denmark

[19] Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark

[20] Aarhus Univ, Dept Clin Med Hlth, Aarhus, Denmark

[21] Aalborg Univ Hosp, Dept Clin Immunol, Aalborg, Denmark

[22] Aalborg Univ, Dept Clin Med, Aalborg, Denmark

[23] Zealand Univ Hosp, Dept Clin Immunol, Koge, Denmark

[24] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark

[25] Statens Serum Inst, Copenhagen, Denmark

[26] Landspitali Univ Hosp, Dept Pediat, Reykjavik, Iceland

[27] Heilsuklasinn Clin, Reykjavik, Iceland

[28] Laeknasetrid Clin, Reykjavik, Iceland

[29] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland

来源：

NATURE GENETICS | 2023年 / 55卷 / 11期

基金：

美国国家卫生研究院; 欧盟地平线“2020”;

关键词：

GENETIC ASSOCIATION; PRRT2; MUTATIONS; LRRK2; EXPRESSION; HEADACHE; POWER; METAANALYSIS; DYSFUNCTION; PREVALENCE;

D O I：

10.1038/s41588-023-01538-0

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1843 / +

页数：16

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