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

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; 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; DBDS Genetic Consortium; Mette Nyegaard; Palle Duun Rohde

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

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 LundOlafur 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, 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^*, DBDS Genetic Consortium, Mette Nyegaard (Medlem af forfattergruppering), Palle Duun Rohde (Medlem af forfattergruppering)

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	55
Udgave nummer	11
Sider (fra-til)	1843-1853
Antal sider	11
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-023-01538-0
Status	Udgivet - nov. 2023

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10.1038/s41588-023-01538-0Licens: CC BY 4.0

Open Access articleForlagets udgivne version, 4,41 MBLicens: CC BY 4.0

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Bjornsdottir, G., Chalmer, M. A., Stefansdottir, L., Skuladottir, A. T., Einarsson, G., Andresdottir, M., Beyter, D., Ferkingstad, E., Gretarsdottir, S., Halldorsson, B. V., Halldorsson, G. H., Helgadottir, A., Helgason, H., Hjorleifsson Eldjarn, G., Jonasdottir, A., Jonasdottir, A., Jonsdottir, I., Knowlton, K. U., Nadauld, L. D., ... Rohde, P. D. (2023). Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura. Nature Genetics, 55(11), 1843-1853. https://doi.org/10.1038/s41588-023-01538-0

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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 Lie, {Rolv T} and Jan Haavik and Karina Banasik and S{\o}ren Brunak and Maria Didriksen and {T Bruun}, Mie and Christian Erikstrup and Kogelman, {Lisette J A} and Nielsen, {Kaspar R} and Erik S{\o}rensen and Pedersen, {Ole B.} and Henrik Ullum and Gisli Masson and Unnur Thorsteinsdottir and Jes Olesen and Petur Ludvigsson and Olafur Thorarensen and Anna Bjornsdottir and Sigurdardottir, {Gudrun R} and Sveinsson, {Olafur A} and Ostrowski, {Sisse R} and Hilma Holm and Gudbjartsson, {Daniel F.} and Gudmar Thorleifsson and Patrick Sulem and Hreinn Stefansson and Thorgeirsson, {Thorgeir E} and Hansen, {Thomas F} and Kari Stefansson and {DBDS Genetic Consortium} and Mette Nyegaard and Rohde, {Palle Duun}",

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year = "2023",

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

language = "English",

volume = "55",

pages = "1843--1853",

journal = "Nature Genetics",

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Bjornsdottir, G, Chalmer, MA, Stefansdottir, L, Skuladottir, AT, Einarsson, G, Andresdottir, M, Beyter, D, Ferkingstad, E, Gretarsdottir, S, Halldorsson, BV, Halldorsson, GH, Helgadottir, A, Helgason, H, Hjorleifsson Eldjarn, G, Jonasdottir, A, Jonasdottir, A, Jonsdottir, I, Knowlton, KU, Nadauld, LD, Lund, SH, Magnusson, OT, Melsted, P, Moore, KHS, Oddsson, A, Olason, PI, Sigurdsson, A, Stefansson, OA, Saemundsdottir, J, Sveinbjornsson, G, Tragante, V, Unnsteinsdottir, U, Walters, GB, Zink, F, Rødevand, L, Andreassen, OA, Igland, J, Lie, RT, Haavik, J, Banasik, K, Brunak, S, Didriksen, M, T Bruun, M, Erikstrup, C, Kogelman, LJA, Nielsen, KR, Sørensen, E, Pedersen, OB, Ullum, H, Masson, G, Thorsteinsdottir, U, Olesen, J, Ludvigsson, P, Thorarensen, O, Bjornsdottir, A, Sigurdardottir, GR, Sveinsson, OA, Ostrowski, SR, Holm, H, Gudbjartsson, DF, Thorleifsson, G, Sulem, P, Stefansson, H, Thorgeirsson, TE, Hansen, TF, Stefansson, K, DBDS Genetic Consortium, Nyegaard, M & Rohde, PD 2023, 'Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura', Nature Genetics, bind 55, nr. 11, s. 1843-1853. https://doi.org/10.1038/s41588-023-01538-0

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 - Lie, Rolv T

AU - Haavik, Jan

AU - Banasik, Karina

AU - Brunak, Søren

AU - Didriksen, Maria

AU - T Bruun, Mie

AU - Erikstrup, Christian

AU - Kogelman, Lisette J A

AU - Nielsen, Kaspar R

AU - Sørensen, Erik

AU - Pedersen, Ole B.

AU - Ullum, Henrik

AU - Masson, Gisli

AU - Thorsteinsdottir, Unnur

AU - Olesen, Jes

AU - Ludvigsson, Petur

AU - Thorarensen, Olafur

AU - Bjornsdottir, Anna

AU - Sigurdardottir, Gudrun R

AU - Sveinsson, Olafur A

AU - Ostrowski, Sisse R

AU - Holm, Hilma

AU - Gudbjartsson, Daniel F.

AU - Thorleifsson, Gudmar

AU - Sulem, Patrick

AU - Stefansson, Hreinn

AU - Thorgeirsson, Thorgeir E

AU - Hansen, Thomas F

AU - Stefansson, Kari

AU - DBDS Genetic Consortium

A2 - Nyegaard, Mette

A2 - Rohde, Palle Duun

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

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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