Genome-wide association analysis identifies susceptibility loci for migraine without aura

Tobias Freilinger; Verneri Anttila; Boukje De Vries; Rainer Malik; Mikko Kallela; Gisela M. Terwindt; Patricia Pozo-Rosich; Bendik Winsvold; Dale R. Nyholt; Willebrordus P.J. Van Oosterhout; Ville Artto; Unda Todt; Eija Hämäläinen; Jèssica Fernández-Morales; Mark A. Louter; Mari A. Kaunisto; Jean Schoenen; Olli Raitakari; Terho Lehtimäki; Marta Vila-Pueyo; Hartmut Göbel; Erich Wichmann; Cèlia Sintas; Andre G. Uitterlinden; Albert Hofman; Fernando Rivadeneira; Axel Heinze; Erling Tronvik; Cornelia M. Van Duijn; Jaakko Kaprio; Bru Cormand; Maija Wessman; Rune R. Frants; Thomas Meitinger; Bertram Müller-Myhsok; John Anker Zwart; Markus Färkkilä; Alfons MacAya; Michel D. Ferrari; Christian Kubisch; Aarno Palotie; Martin Dichgans; Arn M.J.M. Van Den Maagdenberg

doi:10.1038/ng.2307

Genome-wide association analysis identifies susceptibility loci for migraine without aura

Tobias Freilinger, Verneri Anttila, Boukje De Vries, Rainer Malik, Mikko Kallela, Gisela M. Terwindt, Patricia Pozo-Rosich, Bendik Winsvold, Dale R. Nyholt, Willebrordus P.J. Van Oosterhout, Ville Artto, Unda Todt, Eija Hämäläinen, Jèssica Fernández-Morales, Mark A. Louter, Mari A. Kaunisto, Jean Schoenen, Olli Raitakari, Terho Lehtimäki, Marta Vila-PueyoHartmut Göbel, Erich Wichmann, Cèlia Sintas, Andre G. Uitterlinden, Albert Hofman, Fernando Rivadeneira, Axel Heinze, Erling Tronvik, Cornelia M. Van Duijn, Jaakko Kaprio, Bru Cormand, Maija Wessman, Rune R. Frants, Thomas Meitinger, Bertram Müller-Myhsok, John Anker Zwart, Markus Färkkilä, Alfons MacAya, Michel D. Ferrari, Christian Kubisch, Aarno Palotie, Martin Dichgans, Arn M.J.M. Van Den Maagdenberg

Research output: Contribution to journal › Article › peer-review

269 Scopus citations

Abstract

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10-5 for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10-4; combined P = 7.06 × 10-11) and at 3p24 (near TGFBR2; replication P = 1.0 × 10-4; combined P = 1.17 × 10-9). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10-8 and P = 0.02; combined P = 3.86 × 10-8, respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

Original language	English
Pages (from-to)	777-782
Number of pages	6
Journal	Nature Genetics
Volume	44
Issue number	7
DOIs	https://doi.org/10.1038/ng.2307
State	Published - Jul 2012
Externally published	Yes

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Freilinger, T., Anttila, V., De Vries, B., Malik, R., Kallela, M., Terwindt, G. M., Pozo-Rosich, P., Winsvold, B., Nyholt, D. R., Van Oosterhout, W. P. J., Artto, V., Todt, U., Hämäläinen, E., Fernández-Morales, J., Louter, M. A., Kaunisto, M. A., Schoenen, J., Raitakari, O., Lehtimäki, T., ... Van Den Maagdenberg, A. M. J. M. (2012). Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nature Genetics, 44(7), 777-782. https://doi.org/10.1038/ng.2307

@article{f9b53c77cce84afb8bf65a58aff7e135,

title = "Genome-wide association analysis identifies susceptibility loci for migraine without aura",

abstract = "Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10-5 for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10-4; combined P = 7.06 × 10-11) and at 3p24 (near TGFBR2; replication P = 1.0 × 10-4; combined P = 1.17 × 10-9). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10-8 and P = 0.02; combined P = 3.86 × 10-8, respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.",

author = "Tobias Freilinger and Verneri Anttila and {De Vries}, Boukje and Rainer Malik and Mikko Kallela and Terwindt, {Gisela M.} and Patricia Pozo-Rosich and Bendik Winsvold and Nyholt, {Dale R.} and {Van Oosterhout}, {Willebrordus P.J.} and Ville Artto and Unda Todt and Eija H{\"a}m{\"a}l{\"a}inen and J{\`e}ssica Fern{\'a}ndez-Morales and Louter, {Mark A.} and Kaunisto, {Mari A.} and Jean Schoenen and Olli Raitakari and Terho Lehtim{\"a}ki and Marta Vila-Pueyo and Hartmut G{\"o}bel and Erich Wichmann and C{\`e}lia Sintas and Uitterlinden, {Andre G.} and Albert Hofman and Fernando Rivadeneira and Axel Heinze and Erling Tronvik and {Van Duijn}, {Cornelia M.} and Jaakko Kaprio and Bru Cormand and Maija Wessman and Frants, {Rune R.} and Thomas Meitinger and Bertram M{\"u}ller-Myhsok and Zwart, {John Anker} and Markus F{\"a}rkkil{\"a} and Alfons MacAya and Ferrari, {Michel D.} and Christian Kubisch and Aarno Palotie and Martin Dichgans and {Van Den Maagdenberg}, {Arn M.J.M.}",

note = "Funding Information: We wish to thank all individuals in the respective cohorts for their generous participation. This work was supported by the German Federal Ministry of Education and Research (BMBF) (grant 01GS08121 to M.D., along with support to E.W. in the context of the German National Genome Research Network, (NGFN-2 and NGFN-plus) for the Heinz Nixdorf Recall Study); the Spanish Ministry of Science and Innovation (grant SAF2009-13182-C03 to A.M. and B.C.); the Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca (AGAUR) (grants 2009SGR78 and 2009SGR971 to A.M. and B.C., respectively); an unrestricted grant of the Vascular Dementia Research Foundation (to M.D.); the Netherlands Organization for Health Research and Development (ZonMw) (90700217) and VIDI (ZonMw) (91711319 to G.M.T.); the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants (to M.D.F.); the Center for Medical Systems Biology (CMSB) established in the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO) (project 050-060-409 to C.M.v.D., R.R.F., M.D.F. and A.M.J.M.v.d.M. and 050-060-810 to C.M.v.D.) and the generation and management of GWAS genotype data for the Rotterdam Study (175.010.2005.011 and 911-03-012) (funded by the Erasmus Medical Center, Erasmus University Rotterdam and the Ministries of Education, Culture and Science, Health, Welfare and Sports), as well as the NGI-sponsored Netherlands Consortium for Healthy Aging (NCHA) and the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the German Federal Ministry of Education and Research (BMBF) within the framework of the National Genome Research Network (NGFN-Plus; grants 01GS08120 and 01GS1103 to C.K.); the German Federal Ministry of Education and Research and the State of Bavaria, supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ) for the KORA research platform, which was initiated by the Helmholtz Center Munich, German Research Center for Environmental Health; the National Health and Medical Research Council (NHMRC) Research Fellowship (613674) and the Australian Research Council (ARC) Future Fellowship (FT0991022) schemes (to D.R.N.); the Wellcome Trust (grant 098051 to A.P.); the Academy of Finland (grant 251704 to A.P. and 139795 to M.W.); the Academy of Finland, Center of Excellence in Complex Disease Genetics (grants 213506 and 129680 to A.P. and J.K.); the South-Eastern Norway Regional Health Authority (2010075 and 2011083 to B.W. and J.-A.Z.), the Unger-Vetlesen Medical Fund (to B.W.) and the Ullevaal fund (to B.W.); the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013), the ENGAGE Consortium, (grant agreement HEALTH-F4-2007-201413); EU/SYNSYS–Synaptic Systems (grant 242167 to A.P.); the Sigrid Juselius Foundation, Finland (to A.P.); the Folkh{\"a}lsan Research Foundation, Helsinki (to M.W.); and the Helsinki University Central Hospital (to M.K., V. Artto and M.F.).",

year = "2012",

month = jul,

doi = "10.1038/ng.2307",

language = "English",

volume = "44",

pages = "777--782",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

}

Freilinger, T, Anttila, V, De Vries, B, Malik, R, Kallela, M, Terwindt, GM, Pozo-Rosich, P, Winsvold, B, Nyholt, DR, Van Oosterhout, WPJ, Artto, V, Todt, U, Hämäläinen, E, Fernández-Morales, J, Louter, MA, Kaunisto, MA, Schoenen, J, Raitakari, O, Lehtimäki, T, Vila-Pueyo, M, Göbel, H, Wichmann, E, Sintas, C, Uitterlinden, AG, Hofman, A, Rivadeneira, F, Heinze, A, Tronvik, E, Van Duijn, CM, Kaprio, J, Cormand, B, Wessman, M, Frants, RR, Meitinger, T, Müller-Myhsok, B, Zwart, JA, Färkkilä, M, MacAya, A, Ferrari, MD, Kubisch, C, Palotie, A, Dichgans, M & Van Den Maagdenberg, AMJM 2012, 'Genome-wide association analysis identifies susceptibility loci for migraine without aura', Nature Genetics, vol. 44, no. 7, pp. 777-782. https://doi.org/10.1038/ng.2307

TY - JOUR

T1 - Genome-wide association analysis identifies susceptibility loci for migraine without aura

AU - Freilinger, Tobias

AU - Anttila, Verneri

AU - De Vries, Boukje

AU - Malik, Rainer

AU - Kallela, Mikko

AU - Terwindt, Gisela M.

AU - Pozo-Rosich, Patricia

AU - Winsvold, Bendik

AU - Nyholt, Dale R.

AU - Van Oosterhout, Willebrordus P.J.

AU - Artto, Ville

AU - Todt, Unda

AU - Hämäläinen, Eija

AU - Fernández-Morales, Jèssica

AU - Louter, Mark A.

AU - Kaunisto, Mari A.

AU - Schoenen, Jean

AU - Raitakari, Olli

AU - Lehtimäki, Terho

AU - Vila-Pueyo, Marta

AU - Göbel, Hartmut

AU - Wichmann, Erich

AU - Sintas, Cèlia

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Heinze, Axel

AU - Tronvik, Erling

AU - Van Duijn, Cornelia M.

AU - Kaprio, Jaakko

AU - Cormand, Bru

AU - Wessman, Maija

AU - Frants, Rune R.

AU - Meitinger, Thomas

AU - Müller-Myhsok, Bertram

AU - Zwart, John Anker

AU - Färkkilä, Markus

AU - MacAya, Alfons

AU - Ferrari, Michel D.

AU - Kubisch, Christian

AU - Palotie, Aarno

AU - Dichgans, Martin

AU - Van Den Maagdenberg, Arn M.J.M.

N1 - Funding Information: We wish to thank all individuals in the respective cohorts for their generous participation. This work was supported by the German Federal Ministry of Education and Research (BMBF) (grant 01GS08121 to M.D., along with support to E.W. in the context of the German National Genome Research Network, (NGFN-2 and NGFN-plus) for the Heinz Nixdorf Recall Study); the Spanish Ministry of Science and Innovation (grant SAF2009-13182-C03 to A.M. and B.C.); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (grants 2009SGR78 and 2009SGR971 to A.M. and B.C., respectively); an unrestricted grant of the Vascular Dementia Research Foundation (to M.D.); the Netherlands Organization for Health Research and Development (ZonMw) (90700217) and VIDI (ZonMw) (91711319 to G.M.T.); the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants (to M.D.F.); the Center for Medical Systems Biology (CMSB) established in the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO) (project 050-060-409 to C.M.v.D., R.R.F., M.D.F. and A.M.J.M.v.d.M. and 050-060-810 to C.M.v.D.) and the generation and management of GWAS genotype data for the Rotterdam Study (175.010.2005.011 and 911-03-012) (funded by the Erasmus Medical Center, Erasmus University Rotterdam and the Ministries of Education, Culture and Science, Health, Welfare and Sports), as well as the NGI-sponsored Netherlands Consortium for Healthy Aging (NCHA) and the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the German Federal Ministry of Education and Research (BMBF) within the framework of the National Genome Research Network (NGFN-Plus; grants 01GS08120 and 01GS1103 to C.K.); the German Federal Ministry of Education and Research and the State of Bavaria, supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ) for the KORA research platform, which was initiated by the Helmholtz Center Munich, German Research Center for Environmental Health; the National Health and Medical Research Council (NHMRC) Research Fellowship (613674) and the Australian Research Council (ARC) Future Fellowship (FT0991022) schemes (to D.R.N.); the Wellcome Trust (grant 098051 to A.P.); the Academy of Finland (grant 251704 to A.P. and 139795 to M.W.); the Academy of Finland, Center of Excellence in Complex Disease Genetics (grants 213506 and 129680 to A.P. and J.K.); the South-Eastern Norway Regional Health Authority (2010075 and 2011083 to B.W. and J.-A.Z.), the Unger-Vetlesen Medical Fund (to B.W.) and the Ullevaal fund (to B.W.); the European Community’s Seventh Framework Programme (FP7/2007-2013), the ENGAGE Consortium, (grant agreement HEALTH-F4-2007-201413); EU/SYNSYS–Synaptic Systems (grant 242167 to A.P.); the Sigrid Juselius Foundation, Finland (to A.P.); the Folkhälsan Research Foundation, Helsinki (to M.W.); and the Helsinki University Central Hospital (to M.K., V. Artto and M.F.).

PY - 2012/7

Y1 - 2012/7

N2 - Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10-5 for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10-4; combined P = 7.06 × 10-11) and at 3p24 (near TGFBR2; replication P = 1.0 × 10-4; combined P = 1.17 × 10-9). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10-8 and P = 0.02; combined P = 3.86 × 10-8, respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

AB - Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10-5 for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10-4; combined P = 7.06 × 10-11) and at 3p24 (near TGFBR2; replication P = 1.0 × 10-4; combined P = 1.17 × 10-9). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10-8 and P = 0.02; combined P = 3.86 × 10-8, respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

UR - http://www.scopus.com/inward/record.url?scp=84862976129&partnerID=8YFLogxK

U2 - 10.1038/ng.2307

DO - 10.1038/ng.2307

M3 - Article

C2 - 22683712

AN - SCOPUS:84862976129

SN - 1061-4036

VL - 44

SP - 777

EP - 782

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Genome-wide association analysis identifies susceptibility loci for migraine without aura

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