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; Karina Banasik; Søren Brunak; Maria Didriksen; Lisette J.A. Kogelman; Kaspar R. Nielsen; Erik Sørensen; Ole B. Pedersen; Henrik Ullum; Jakob Bay; Kristoffer Burgdorf; Joseph Dowsett; Henrik Hjalgrim; Rikke L. Jacobsen; Ioannis Louloudis; Agnete Lundgaard; Christina Mikkelsen; Mette Nyegaard; Alexander P. Henriksen; Thomas Werge; David Westergaard; Jes Olesen; Sisse R. Ostrowski; Thomas F. Hansen; 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

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, Karina Banasik, Søren Brunak, Maria Didriksen, Lisette J.A. Kogelman, Kaspar R. Nielsen, Erik Sørensen, Ole B. Pedersen, Henrik Ullum, Jakob Bay, Kristoffer Burgdorf, Joseph Dowsett, Henrik Hjalgrim, Rikke L. Jacobsen, Ioannis Louloudis, Agnete Lundgaard, Christina Mikkelsen, Mette Nyegaard, Alexander P. Henriksen, Thomas Werge, David Westergaard, Jes Olesen, Sisse R. Ostrowski, Thomas F. Hansen, DBDS Genetic Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › 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.

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

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Publisher Copyright:
© 2023, The Author(s).

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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., ... DBDS Genetic Consortium (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

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura. / 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; Banasik, Karina ; Brunak, Søren ; Didriksen, Maria; Kogelman, Lisette J.A.; Nielsen, Kaspar R.; Sørensen, Erik; Pedersen, Ole B.; Ullum, Henrik; Bay, Jakob; Burgdorf, Kristoffer; Dowsett, Joseph; Hjalgrim, Henrik; Jacobsen, Rikke L.; Louloudis, Ioannis ; Lundgaard, Agnete ; Mikkelsen, Christina; Nyegaard, Mette; Henriksen, Alexander P.; Werge, Thomas; Westergaard, David; Olesen, Jes ; Ostrowski, Sisse R.; Hansen, Thomas F.; DBDS Genetic Consortium.

In: Nature Genetics, Vol. 55, No. 11, 2023, p. 1843-1853.

Research output: Contribution to journal › Journal article › Research › peer-review

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, Banasik, K , Brunak, S , Didriksen, M, Kogelman, LJA, Nielsen, KR, Sørensen, E, Pedersen, OB, Ullum, H, Bay, J, Burgdorf, K, Dowsett, J, Hjalgrim, H, Jacobsen, RL, Louloudis, I , Lundgaard, A , Mikkelsen, C, Nyegaard, M, Henriksen, AP , Werge, T, Westergaard, D, Olesen, J , Ostrowski, SR , Hansen, TF & DBDS Genetic Consortium 2023, 'Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura', Nature Genetics, vol. 55, no. 11, pp. 1843-1853. https://doi.org/10.1038/s41588-023-01538-0

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 ; Banasik, Karina ; Brunak, Søren ; Didriksen, Maria ; Kogelman, Lisette J.A. ; Nielsen, Kaspar R. ; Sørensen, Erik ; Pedersen, Ole B. ; Ullum, Henrik ; Bay, Jakob ; Burgdorf, Kristoffer ; Dowsett, Joseph ; Hjalgrim, Henrik ; Jacobsen, Rikke L. ; Louloudis, Ioannis ; Lundgaard, Agnete ; Mikkelsen, Christina ; Nyegaard, Mette ; Henriksen, Alexander P. ; Werge, Thomas ; Westergaard, David ; Olesen, Jes ; Ostrowski, Sisse R. ; Hansen, Thomas F. ; DBDS Genetic Consortium. / Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura. In: Nature Genetics. 2023 ; Vol. 55, No. 11. pp. 1843-1853.

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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.",

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 Karina Banasik and S{\o}ren Brunak and Maria Didriksen and Kogelman, {Lisette J.A.} and Nielsen, {Kaspar R.} and Erik S{\o}rensen and Pedersen, {Ole B.} and Henrik Ullum and Jakob Bay and Kristoffer Burgdorf and Joseph Dowsett and Henrik Hjalgrim and Jacobsen, {Rikke L.} and Ioannis Louloudis and Agnete Lundgaard and Christina Mikkelsen and Mette Nyegaard and Henriksen, {Alexander P.} and Thomas Werge and David Westergaard and Jes Olesen and Ostrowski, {Sisse R.} and Hansen, {Thomas F.} and {DBDS Genetic Consortium}",

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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

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AU - Lund, Sigrun H.

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AU - Moore, Kristjan H.S.

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AU - Nielsen, Kaspar R.

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AU - Pedersen, Ole B.

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AU - Bay, Jakob

AU - Burgdorf, Kristoffer

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AU - Hjalgrim, Henrik

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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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DO - 10.1038/s41588-023-01538-0

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C2 - 37884687

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JO - Nature Genetics

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