Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants

Bendik S. Winsvold; Francesco Bettella; Aree Witoelar; Verneri Anttila; Padhraig Gormley; Tobias Kurth; Gisela M. Terwindt; Tobias Freilinger; Oleksander Frei; Alexey Shadrin; Yunpeng Wang; Anders M. Dale; Arn M.J.M. van den Maagdenberg; Dale R. Nyholt; Aarno Palotie; Ole A. Andreassen; John Anker Zwart; Ville Artto; Andrea Carmine Belin; Dorret I. Boomsma; Sigrid Børte; Daniel I. Chasman; Lynn Cherkas; Anne Francke Christensen; Bru Cormand; Ester Cuenca-Leon; George Davey-Smith; Martin Dichgans; Cornelia van Duijn; Else Eising; Tonu Esko; Ann Louise Esserlind; Michel Ferrari; Rune R. Frants; Tobias Freilinger; Nick Furlotte; Lyn Griffiths; Eija Hamalainen; Thomas Folkmann Hansen; Marjo Hiekkala; M. Arfan Ikram; Andres Ingason; Marjo Riitta Järvelin; Risto Kajanne; Mikko Kallela; Jaakko Kaprio; Mari Kaunisto; Christian Kubisch; Mitja Kurki; Jes Olesen; International Headache Genetics Consortium

doi:10.1371/journal.pone.0185663

Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants

Bendik S. Winsvold^*, Francesco Bettella, Aree Witoelar, Verneri Anttila, Padhraig Gormley, Tobias Kurth, Gisela M. Terwindt, Tobias Freilinger, Oleksander Frei, Alexey Shadrin, Yunpeng Wang, Anders M. Dale, Arn M.J.M. van den Maagdenberg, Dale R. Nyholt, Aarno Palotie, Ole A. Andreassen, John Anker Zwart, Ville Artto, Andrea Carmine Belin, Dorret I. BoomsmaSigrid Børte, Daniel I. Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Martin Dichgans, Cornelia van Duijn, Else Eising, Tonu Esko, Ann Louise Esserlind, Michel Ferrari, Rune R. Frants, Tobias Freilinger, Nick Furlotte, Lyn Griffiths, Eija Hamalainen, Thomas Folkmann Hansen, Marjo Hiekkala, M. Arfan Ikram, Andres Ingason, Marjo Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Christian Kubisch, Mitja Kurki, Jes Olesen, International Headache Genetics Consortium

^*Corresponding author for this work

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

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Abstract

Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the genetic overlap between migraine and CAD, and to identify shared genetic risk loci, utilizing a conditional false discovery rate approach and data from two large-scale genome-wide association studies (GWAS) of CAD (C4D, 15,420 cases, 15,062 controls; CARDIoGRAM, 22,233 cases, 64,762 controls) and one of migraine (22,120 cases, 91,284 controls). We found significant enrichment of genetic variants associated with CAD as a function of their association with migraine, which was replicated across two independent CAD GWAS studies. One shared risk locus in the PHACTR1 gene (conjunctional false discovery rate for index SNP rs9349379 < 3.90 x 10⁻⁵), which was also identified in previous studies, explained much of the enrichment. Two further loci (in KCNK5 and AS3MT) showed evidence for shared risk (conjunctional false discovery rate < 0.05). The index SNPs at two of the three loci had opposite effect directions in migraine and CAD. Our results confirm previous reports that migraine and CAD share genetic risk loci in excess of what would be expected by chance, and highlight one shared risk locus in PHACTR1. Understanding the biological mechanisms underpinning this shared risk is likely to improve our understanding of both disorders.

Original language	English
Article number	e0185663
Journal	PLoS ONE
Volume	12
Issue number	9
Number of pages	15
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0185663
Publication status	Published - 2017

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Publisher Copyright:
© 2017 Winsvold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Winsvold, B. S., Bettella, F., Witoelar, A., Anttila, V., Gormley, P., Kurth, T., Terwindt, G. M., Freilinger, T., Frei, O., Shadrin, A., Wang, Y., Dale, A. M., van den Maagdenberg, A. M. J. M., Nyholt, D. R., Palotie, A., Andreassen, O. A., Zwart, J. A., Artto, V., Belin, A. C., ... International Headache Genetics Consortium (2017). Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants. PLoS ONE, 12(9), [e0185663]. https://doi.org/10.1371/journal.pone.0185663

Shared genetic risk between migraine and coronary artery disease : A genome-wide analysis of common variants. / Winsvold, Bendik S.; Bettella, Francesco; Witoelar, Aree; Anttila, Verneri; Gormley, Padhraig; Kurth, Tobias; Terwindt, Gisela M.; Freilinger, Tobias; Frei, Oleksander; Shadrin, Alexey; Wang, Yunpeng; Dale, Anders M.; van den Maagdenberg, Arn M.J.M.; Nyholt, Dale R.; Palotie, Aarno; Andreassen, Ole A.; Zwart, John Anker; Artto, Ville; Belin, Andrea Carmine; Boomsma, Dorret I.; Børte, Sigrid; Chasman, Daniel I.; Cherkas, Lynn; Christensen, Anne Francke; Cormand, Bru; Cuenca-Leon, Ester; Davey-Smith, George; Dichgans, Martin; van Duijn, Cornelia; Eising, Else; Esko, Tonu; Esserlind, Ann Louise; Ferrari, Michel; Frants, Rune R.; Freilinger, Tobias; Furlotte, Nick; Griffiths, Lyn; Hamalainen, Eija; Hansen, Thomas Folkmann; Hiekkala, Marjo; Arfan Ikram, M.; Ingason, Andres; Järvelin, Marjo Riitta; Kajanne, Risto; Kallela, Mikko; Kaprio, Jaakko; Kaunisto, Mari; Kubisch, Christian; Kurki, Mitja; Olesen, Jes; International Headache Genetics Consortium.

In: PLoS ONE, Vol. 12, No. 9, e0185663, 2017.

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

Winsvold, BS, Bettella, F, Witoelar, A, Anttila, V, Gormley, P, Kurth, T, Terwindt, GM, Freilinger, T, Frei, O, Shadrin, A, Wang, Y, Dale, AM, van den Maagdenberg, AMJM, Nyholt, DR, Palotie, A, Andreassen, OA, Zwart, JA, Artto, V, Belin, AC, Boomsma, DI, Børte, S, Chasman, DI, Cherkas, L, Christensen, AF, Cormand, B, Cuenca-Leon, E, Davey-Smith, G, Dichgans, M, van Duijn, C, Eising, E, Esko, T, Esserlind, AL, Ferrari, M, Frants, RR, Freilinger, T, Furlotte, N, Griffiths, L, Hamalainen, E, Hansen, TF, Hiekkala, M, Arfan Ikram, M, Ingason, A, Järvelin, MR, Kajanne, R, Kallela, M, Kaprio, J, Kaunisto, M, Kubisch, C, Kurki, M, Olesen, J & International Headache Genetics Consortium 2017, 'Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants', PLoS ONE, vol. 12, no. 9, e0185663. https://doi.org/10.1371/journal.pone.0185663

Winsvold, Bendik S. ; Bettella, Francesco ; Witoelar, Aree ; Anttila, Verneri ; Gormley, Padhraig ; Kurth, Tobias ; Terwindt, Gisela M. ; Freilinger, Tobias ; Frei, Oleksander ; Shadrin, Alexey ; Wang, Yunpeng ; Dale, Anders M. ; van den Maagdenberg, Arn M.J.M. ; Nyholt, Dale R. ; Palotie, Aarno ; Andreassen, Ole A. ; Zwart, John Anker ; Artto, Ville ; Belin, Andrea Carmine ; Boomsma, Dorret I. ; Børte, Sigrid ; Chasman, Daniel I. ; Cherkas, Lynn ; Christensen, Anne Francke ; Cormand, Bru ; Cuenca-Leon, Ester ; Davey-Smith, George ; Dichgans, Martin ; van Duijn, Cornelia ; Eising, Else ; Esko, Tonu ; Esserlind, Ann Louise ; Ferrari, Michel ; Frants, Rune R. ; Freilinger, Tobias ; Furlotte, Nick ; Griffiths, Lyn ; Hamalainen, Eija ; Hansen, Thomas Folkmann ; Hiekkala, Marjo ; Arfan Ikram, M. ; Ingason, Andres ; Järvelin, Marjo Riitta ; Kajanne, Risto ; Kallela, Mikko ; Kaprio, Jaakko ; Kaunisto, Mari ; Kubisch, Christian ; Kurki, Mitja ; Olesen, Jes ; International Headache Genetics Consortium. / Shared genetic risk between migraine and coronary artery disease : A genome-wide analysis of common variants. In: PLoS ONE. 2017 ; Vol. 12, No. 9.

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title = "Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants",

abstract = "Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the genetic overlap between migraine and CAD, and to identify shared genetic risk loci, utilizing a conditional false discovery rate approach and data from two large-scale genome-wide association studies (GWAS) of CAD (C4D, 15,420 cases, 15,062 controls; CARDIoGRAM, 22,233 cases, 64,762 controls) and one of migraine (22,120 cases, 91,284 controls). We found significant enrichment of genetic variants associated with CAD as a function of their association with migraine, which was replicated across two independent CAD GWAS studies. One shared risk locus in the PHACTR1 gene (conjunctional false discovery rate for index SNP rs9349379 < 3.90 x 10−5), which was also identified in previous studies, explained much of the enrichment. Two further loci (in KCNK5 and AS3MT) showed evidence for shared risk (conjunctional false discovery rate < 0.05). The index SNPs at two of the three loci had opposite effect directions in migraine and CAD. Our results confirm previous reports that migraine and CAD share genetic risk loci in excess of what would be expected by chance, and highlight one shared risk locus in PHACTR1. Understanding the biological mechanisms underpinning this shared risk is likely to improve our understanding of both disorders.",

author = "Winsvold, {Bendik S.} and Francesco Bettella and Aree Witoelar and Verneri Anttila and Padhraig Gormley and Tobias Kurth and Terwindt, {Gisela M.} and Tobias Freilinger and Oleksander Frei and Alexey Shadrin and Yunpeng Wang and Dale, {Anders M.} and {van den Maagdenberg}, {Arn M.J.M.} and Nyholt, {Dale R.} and Aarno Palotie and Andreassen, {Ole A.} and Zwart, {John Anker} and Ville Artto and Belin, {Andrea Carmine} and Boomsma, {Dorret I.} and Sigrid B{\o}rte and Chasman, {Daniel I.} and Lynn Cherkas and Christensen, {Anne Francke} and Bru Cormand and Ester Cuenca-Leon and George Davey-Smith and Martin Dichgans and {van Duijn}, Cornelia and Else Eising and Tonu Esko and Esserlind, {Ann Louise} and Michel Ferrari and Frants, {Rune R.} and Tobias Freilinger and Nick Furlotte and Lyn Griffiths and Eija Hamalainen and Hansen, {Thomas Folkmann} and Marjo Hiekkala and {Arfan Ikram}, M. and Andres Ingason and J{\"a}rvelin, {Marjo Riitta} and Risto Kajanne and Mikko Kallela and Jaakko Kaprio and Mari Kaunisto and Christian Kubisch and Mitja Kurki and Jes Olesen and {International Headache Genetics Consortium}",

note = "Publisher Copyright: {\textcopyright} 2017 Winsvold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2017",

doi = "10.1371/journal.pone.0185663",

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T1 - Shared genetic risk between migraine and coronary artery disease

T2 - A genome-wide analysis of common variants

AU - Winsvold, Bendik S.

AU - Bettella, Francesco

AU - Witoelar, Aree

AU - Anttila, Verneri

AU - Gormley, Padhraig

AU - Kurth, Tobias

AU - Terwindt, Gisela M.

AU - Freilinger, Tobias

AU - Frei, Oleksander

AU - Shadrin, Alexey

AU - Wang, Yunpeng

AU - Dale, Anders M.

AU - van den Maagdenberg, Arn M.J.M.

AU - Nyholt, Dale R.

AU - Palotie, Aarno

AU - Andreassen, Ole A.

AU - Zwart, John Anker

AU - Artto, Ville

AU - Belin, Andrea Carmine

AU - Boomsma, Dorret I.

AU - Børte, Sigrid

AU - Chasman, Daniel I.

AU - Cherkas, Lynn

AU - Christensen, Anne Francke

AU - Cormand, Bru

AU - Cuenca-Leon, Ester

AU - Davey-Smith, George

AU - Dichgans, Martin

AU - van Duijn, Cornelia

AU - Eising, Else

AU - Esko, Tonu

AU - Esserlind, Ann Louise

AU - Ferrari, Michel

AU - Frants, Rune R.

AU - Freilinger, Tobias

AU - Furlotte, Nick

AU - Griffiths, Lyn

AU - Hamalainen, Eija

AU - Hansen, Thomas Folkmann

AU - Hiekkala, Marjo

AU - Arfan Ikram, M.

AU - Ingason, Andres

AU - Järvelin, Marjo Riitta

AU - Kajanne, Risto

AU - Kallela, Mikko

AU - Kaprio, Jaakko

AU - Kaunisto, Mari

AU - Kubisch, Christian

AU - Kurki, Mitja

AU - Olesen, Jes

AU - International Headache Genetics Consortium

N1 - Publisher Copyright: © 2017 Winsvold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2017

Y1 - 2017

N2 - Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the genetic overlap between migraine and CAD, and to identify shared genetic risk loci, utilizing a conditional false discovery rate approach and data from two large-scale genome-wide association studies (GWAS) of CAD (C4D, 15,420 cases, 15,062 controls; CARDIoGRAM, 22,233 cases, 64,762 controls) and one of migraine (22,120 cases, 91,284 controls). We found significant enrichment of genetic variants associated with CAD as a function of their association with migraine, which was replicated across two independent CAD GWAS studies. One shared risk locus in the PHACTR1 gene (conjunctional false discovery rate for index SNP rs9349379 < 3.90 x 10−5), which was also identified in previous studies, explained much of the enrichment. Two further loci (in KCNK5 and AS3MT) showed evidence for shared risk (conjunctional false discovery rate < 0.05). The index SNPs at two of the three loci had opposite effect directions in migraine and CAD. Our results confirm previous reports that migraine and CAD share genetic risk loci in excess of what would be expected by chance, and highlight one shared risk locus in PHACTR1. Understanding the biological mechanisms underpinning this shared risk is likely to improve our understanding of both disorders.

AB - Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the genetic overlap between migraine and CAD, and to identify shared genetic risk loci, utilizing a conditional false discovery rate approach and data from two large-scale genome-wide association studies (GWAS) of CAD (C4D, 15,420 cases, 15,062 controls; CARDIoGRAM, 22,233 cases, 64,762 controls) and one of migraine (22,120 cases, 91,284 controls). We found significant enrichment of genetic variants associated with CAD as a function of their association with migraine, which was replicated across two independent CAD GWAS studies. One shared risk locus in the PHACTR1 gene (conjunctional false discovery rate for index SNP rs9349379 < 3.90 x 10−5), which was also identified in previous studies, explained much of the enrichment. Two further loci (in KCNK5 and AS3MT) showed evidence for shared risk (conjunctional false discovery rate < 0.05). The index SNPs at two of the three loci had opposite effect directions in migraine and CAD. Our results confirm previous reports that migraine and CAD share genetic risk loci in excess of what would be expected by chance, and highlight one shared risk locus in PHACTR1. Understanding the biological mechanisms underpinning this shared risk is likely to improve our understanding of both disorders.

U2 - 10.1371/journal.pone.0185663

DO - 10.1371/journal.pone.0185663

M3 - Journal article

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VL - 12

JO - PLoS ONE

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