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

DBDS Genetic Consortium

doi:10.1038/s41588-023-01538-0

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

DBDS Genetic Consortium

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	Nature Genetics
Volume	55
Issue	11
Pages (from-to)	1843-1853
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-023-01538-0
Publication status	Published - Nov 2023

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@article{da5cf8e1d18042d9a4399252daeb6322,

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

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.",

author = "Gyda Bjornsdottir and Chalmer, {Mona A.} and Lilja Stefansdottir and Skuladottir, {Astros Th} and Gudmundur Einarsson and Margret Andresdottir and Doruk Beyter and Egil Ferkingstad and Solveig Gretarsdottir and Halldorsson, {Bjarni V.} and Halldorsson, {Gisli H.} and Anna Helgadottir and Hannes Helgason and {Hjorleifsson Eldjarn}, Grimur and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Ingileif Jonsdottir and Knowlton, {Kirk U.} and Nadauld, {Lincoln D.} and Lund, {Sigrun H.} and Magnusson, {Olafur Th} and Pall Melsted and Moore, {Kristjan H.S.} and Asmundur Oddsson and Olason, {Pall I.} and Asgeir Sigurdsson and Stefansson, {Olafur A.} and Jona Saemundsdottir and Gardar Sveinbjornsson and Vinicius Tragante and Unnur Unnsteinsdottir and Walters, {G. Bragi} and Florian Zink and Linn R{\o}devand and Andreassen, {Ole A.} and Jannicke Igland and Christian Erikstrup and Nielsen, {Kaspar R.} and Erik S{\o}rensen and Pedersen, {Ole B.} and Boldsen, {Jens K.} and Dinh, {Khoa M.} and Lotte Hindhede and Jacobsen, {Rikke L.} and Katrine Kaspersen and Susan Mikkelsen and Christina Mikkelsen and Mette Nyegaard and Rohde, {Palle D.} and Hansen, {Thomas F.} and {DBDS Genetic Consortium} and Kaspersen, {Kathrine Agerg{\aa}rd}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = nov,

doi = "10.1038/s41588-023-01538-0",

language = "English",

volume = "55",

pages = "1843--1853",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

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TY - JOUR

T1 - Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

AU - Bjornsdottir, Gyda

AU - Chalmer, Mona A.

AU - Stefansdottir, Lilja

AU - Skuladottir, Astros Th

AU - Einarsson, Gudmundur

AU - Andresdottir, Margret

AU - Beyter, Doruk

AU - Ferkingstad, Egil

AU - Gretarsdottir, Solveig

AU - Halldorsson, Bjarni V.

AU - Halldorsson, Gisli H.

AU - Helgadottir, Anna

AU - Helgason, Hannes

AU - Hjorleifsson Eldjarn, Grimur

AU - Jonasdottir, Adalbjorg

AU - Jonasdottir, Aslaug

AU - Jonsdottir, Ingileif

AU - Knowlton, Kirk U.

AU - Nadauld, Lincoln D.

AU - Lund, Sigrun H.

AU - Magnusson, Olafur Th

AU - Melsted, Pall

AU - Moore, Kristjan H.S.

AU - Oddsson, Asmundur

AU - Olason, Pall I.

AU - Sigurdsson, Asgeir

AU - Stefansson, Olafur A.

AU - Saemundsdottir, Jona

AU - Sveinbjornsson, Gardar

AU - Tragante, Vinicius

AU - Unnsteinsdottir, Unnur

AU - Walters, G. Bragi

AU - Zink, Florian

AU - Rødevand, Linn

AU - Andreassen, Ole A.

AU - Igland, Jannicke

AU - Erikstrup, Christian

AU - Nielsen, Kaspar R.

AU - Sørensen, Erik

AU - Pedersen, Ole B.

AU - Boldsen, Jens K.

AU - Dinh, Khoa M.

AU - Hindhede, Lotte

AU - Jacobsen, Rikke L.

AU - Kaspersen, Katrine

AU - Mikkelsen, Susan

AU - Mikkelsen, Christina

AU - Nyegaard, Mette

AU - Rohde, Palle D.

AU - Hansen, Thomas F.

AU - DBDS Genetic Consortium

AU - Kaspersen, Kathrine Agergård

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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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U2 - 10.1038/s41588-023-01538-0

DO - 10.1038/s41588-023-01538-0

M3 - Journal article

C2 - 37884687

AN - SCOPUS:85174915851

SN - 1061-4036

VL - 55

SP - 1843

EP - 1853

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

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