Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Padhraig Gormley; Verneri Anttila; Bendik S. Winsvold; Priit Palta; Tonu Esko; Tune H. Pers; Kai-How Farh; Ester Cuenca-Leon; Mikko Muona; Nicholas A. Furlotte; Tobias Kurth; Andres Ingason; George McMahon; Lannie Ligthart; Gisela M. Terwindt; Mikko Kallela; Tobias M. Freilinger; Caroline Ran; Scott G. Gordon; Anine H. Stam; Stacy Steinberg; Guntram Borck; Markku Koiranen; Lydia Quaye; Hieab H. H. Adams; Terho Lehtimaki; Antti-Pekka Sarin; Juho Wedenoja; David A. Hinds; Julie E. Buring; Markus Schurks; Paul M. Ridker; Maria Gudlaug Hrafnsdottir; Hreinn Stefansson; Susan M. Ring; Jouke-Jan Hottenga; Brenda W. J. H. Penninx; Markus Farkkila; Ville Artto; Mari Kaunisto; Salli Vepsalainen; Rainer Malik; Andrew C. Heath; Pamela A. F. Madden; Nicholas G. Martin; Grant W. Montgomery; Mitja I. Kurki; Mart Kals; Reedik Magi; Kalle Parn; Eija Hamalainen; Hailiang Huang; Andrea E. Byrnes; Lude Franke; Jie Huang; Evie Stergiakouli; Phil H. Lee; Cynthia Sandor; Caleb Webber; Zameel Cader; Bertram Muller-Myhsok; Stefan Schreiber; Thomas Meitinger; Johan G. Eriksson; Veikko Salomaa; Kauko Heikkila; Elizabeth Loehrer; Andre G. Uitterlinden; Albert Hofman; Cornelia M. van Duijn; Lynn Cherkas; Linda M. Pedersen; Audun Stubhaug; Christopher S. Nielsen; Minna Mannikko; Evelin Mihailov; Lili Milani; Hartmut Gobel; Ann-Louise Esserlind; Anne Francke Christensen; Thomas Folkmann Hansen; Thomas Werge; Jaakko Kaprio; Arpo J. Aromaa; Olli Raitakari; M. Arfan Ikram; Tim Spector; Marjo-Riitta Jarvelin; Andres Metspalu; Christian Kubisch; David P. Strachan; Michel D. Ferrari; Andrea C. Belin; Martin Dichgans; Maija Wessman; Arn M. J. M. van den Maagdenberg; John-Anker Zwart; Dorret I. Boomsma; George Davey Smith; Kari Stefansson; Nicholas Eriksson; Mark J. Daly; Benjamin M. Neale; Jes Olesen; Daniel I. Chasman; Dale R. Nyholt; Aarno Palotie; D Posthuma; T. Lehtimäki; M. Färkkilä; S. Vepsäläinen; R. Mägi; K. Pärn; E. Hämaläinen; K. Heikkilä; A.G. Loehrer; M. Männikkö; H. Göbel; M.R. Järvelin

doi:https://doi.org/10.1038/ng.3598

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Padhraig Gormley, Verneri Anttila, Bendik S. Winsvold, Priit Palta, Tonu Esko, Tune H. Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A. Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M. Terwindt, Mikko Kallela, Tobias M. Freilinger, Caroline Ran, Scott G. Gordon, Anine H. StamStacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H. H. Adams, Terho Lehtimaki, Antti-Pekka Sarin, Juho Wedenoja, David A. Hinds, Julie E. Buring, Markus Schurks, Paul M. Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M. Ring, Jouke-Jan Hottenga, Brenda W. J. H. Penninx, Markus Farkkila, Ville Artto, Mari Kaunisto, Salli Vepsalainen, Rainer Malik, Andrew C. Heath, Pamela A. F. Madden, Nicholas G. Martin, Grant W. Montgomery, Mitja I. Kurki, Mart Kals, Reedik Magi, Kalle Parn, Eija Hamalainen, Hailiang Huang, Andrea E. Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H. Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G. Eriksson, Veikko Salomaa, Kauko Heikkila, Elizabeth Loehrer, Andre G. Uitterlinden, Albert Hofman, Cornelia M. van Duijn, Lynn Cherkas, Linda M. Pedersen, Audun Stubhaug, Christopher S. Nielsen, Minna Mannikko, Evelin Mihailov, Lili Milani, Hartmut Gobel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J. Aromaa, Olli Raitakari, M. Arfan Ikram, Tim Spector, Marjo-Riitta Jarvelin, Andres Metspalu, Christian Kubisch, David P. Strachan, Michel D. Ferrari, Andrea C. Belin, Martin Dichgans, Maija Wessman, Arn M. J. M. van den Maagdenberg, John-Anker Zwart, Dorret I. Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J. Daly, Benjamin M. Neale, Jes Olesen, Daniel I. Chasman, Dale R. Nyholt, Aarno Palotie, D Posthuma, T. Lehtimäki, M. Färkkilä, S. Vepsäläinen, R. Mägi, K. Pärn, E. Hämaläinen, K. Heikkilä, A.G. Loehrer, M. Männikkö, H. Göbel, M.R. Järvelin

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

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Abstract

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Original language	English
Pages (from-to)	856-866
Journal	Nature Genetics
Volume	48
Issue number	8
DOIs	https://doi.org/10.1038/ng.3598
Publication status	Published - Aug 2016

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https://doi.org/10.1038/ng.3598

Cite this

Gormley, P., Anttila, V., Winsvold, B. S., Palta, P., Esko, T., Pers, T. H., Farh, K-H., Cuenca-Leon, E., Muona, M., Furlotte, N. A., Kurth, T., Ingason, A., McMahon, G., Ligthart, L., Terwindt, G. M., Kallela, M., Freilinger, T. M., Ran, C., Gordon, S. G., ... Järvelin, M. R. (2016). Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nature Genetics, 48(8), 856-866. https://doi.org/10.1038/ng.3598

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title = "Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine",

abstract = "Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.",

author = "Padhraig Gormley and Verneri Anttila and Winsvold, {Bendik S.} and Priit Palta and Tonu Esko and Pers, {Tune H.} and Kai-How Farh and Ester Cuenca-Leon and Mikko Muona and Furlotte, {Nicholas A.} and Tobias Kurth and Andres Ingason and George McMahon and Lannie Ligthart and Terwindt, {Gisela M.} and Mikko Kallela and Freilinger, {Tobias M.} and Caroline Ran and Gordon, {Scott G.} and Stam, {Anine H.} and Stacy Steinberg and Guntram Borck and Markku Koiranen and Lydia Quaye and Adams, {Hieab H. H.} and Terho Lehtimaki and Antti-Pekka Sarin and Juho Wedenoja and Hinds, {David A.} and Buring, {Julie E.} and Markus Schurks and Ridker, {Paul M.} and Hrafnsdottir, {Maria Gudlaug} and Hreinn Stefansson and Ring, {Susan M.} and Jouke-Jan Hottenga and Penninx, {Brenda W. J. H.} and Markus Farkkila and Ville Artto and Mari Kaunisto and Salli Vepsalainen and Rainer Malik and Heath, {Andrew C.} and Madden, {Pamela A. F.} and Martin, {Nicholas G.} and Montgomery, {Grant W.} and Kurki, {Mitja I.} and Mart Kals and Reedik Magi and Kalle Parn and Eija Hamalainen and Hailiang Huang and Byrnes, {Andrea E.} and Lude Franke and Jie Huang and Evie Stergiakouli and Lee, {Phil H.} and Cynthia Sandor and Caleb Webber and Zameel Cader and Bertram Muller-Myhsok and Stefan Schreiber and Thomas Meitinger and Eriksson, {Johan G.} and Veikko Salomaa and Kauko Heikkila and Elizabeth Loehrer and Uitterlinden, {Andre G.} and Albert Hofman and {van Duijn}, {Cornelia M.} and Lynn Cherkas and Pedersen, {Linda M.} and Audun Stubhaug and Nielsen, {Christopher S.} and Minna Mannikko and Evelin Mihailov and Lili Milani and Hartmut Gobel and Ann-Louise Esserlind and Christensen, {Anne Francke} and Hansen, {Thomas Folkmann} and Thomas Werge and Jaakko Kaprio and Aromaa, {Arpo J.} and Olli Raitakari and Ikram, {M. Arfan} and Tim Spector and Marjo-Riitta Jarvelin and Andres Metspalu and Christian Kubisch and Strachan, {David P.} and Ferrari, {Michel D.} and Belin, {Andrea C.} and Martin Dichgans and Maija Wessman and {van den Maagdenberg}, {Arn M. J. M.} and John-Anker Zwart and Boomsma, {Dorret I.} and Smith, {George Davey} and Kari Stefansson and Nicholas Eriksson and Daly, {Mark J.} and Neale, {Benjamin M.} and Jes Olesen and Chasman, {Daniel I.} and Nyholt, {Dale R.} and Aarno Palotie and D Posthuma and T. Lehtim{\"a}ki and M. F{\"a}rkkil{\"a} and S. Veps{\"a}l{\"a}inen and R. M{\"a}gi and K. P{\"a}rn and E. H{\"a}mal{\"a}inen and K. Heikkil{\"a} and A.G. Loehrer and M. M{\"a}nnikk{\"o} and H. G{\"o}bel and M.R. J{\"a}rvelin",

year = "2016",

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doi = "https://doi.org/10.1038/ng.3598",

language = "English",

volume = "48",

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Gormley, P, Anttila, V, Winsvold, BS, Palta, P, Esko, T, Pers, TH, Farh, K-H, Cuenca-Leon, E, Muona, M, Furlotte, NA, Kurth, T, Ingason, A, McMahon, G, Ligthart, L, Terwindt, GM, Kallela, M, Freilinger, TM, Ran, C, Gordon, SG, Stam, AH, Steinberg, S, Borck, G, Koiranen, M, Quaye, L, Adams, HHH, Lehtimaki, T, Sarin, A-P, Wedenoja, J, Hinds, DA, Buring, JE, Schurks, M, Ridker, PM, Hrafnsdottir, MG, Stefansson, H, Ring, SM, Hottenga, J-J, Penninx, BWJH, Farkkila, M, Artto, V, Kaunisto, M, Vepsalainen, S, Malik, R, Heath, AC, Madden, PAF, Martin, NG, Montgomery, GW, Kurki, MI, Kals, M, Magi, R, Parn, K, Hamalainen, E, Huang, H, Byrnes, AE, Franke, L, Huang, J, Stergiakouli, E, Lee, PH, Sandor, C, Webber, C, Cader, Z, Muller-Myhsok, B, Schreiber, S, Meitinger, T, Eriksson, JG, Salomaa, V, Heikkila, K, Loehrer, E, Uitterlinden, AG, Hofman, A, van Duijn, CM, Cherkas, L, Pedersen, LM, Stubhaug, A, Nielsen, CS, Mannikko, M, Mihailov, E, Milani, L, Gobel, H, Esserlind, A-L, Christensen, AF, Hansen, TF, Werge, T, Kaprio, J, Aromaa, AJ, Raitakari, O, Ikram, MA, Spector, T, Jarvelin, M-R, Metspalu, A, Kubisch, C, Strachan, DP, Ferrari, MD, Belin, AC, Dichgans, M, Wessman, M, van den Maagdenberg, AMJM, Zwart, J-A, Boomsma, DI, Smith, GD, Stefansson, K, Eriksson, N, Daly, MJ, Neale, BM, Olesen, J, Chasman, DI, Nyholt, DR, Palotie, A, Posthuma, D, Lehtimäki, T, Färkkilä, M, Vepsäläinen, S, Mägi, R, Pärn, K, Hämaläinen, E, Heikkilä, K, Loehrer, AG, Männikkö, M, Göbel, H & Järvelin, MR 2016, 'Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine', Nature Genetics, vol. 48, no. 8, pp. 856-866. https://doi.org/10.1038/ng.3598

TY - JOUR

T1 - Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

AU - Gormley, Padhraig

AU - Anttila, Verneri

AU - Winsvold, Bendik S.

AU - Palta, Priit

AU - Esko, Tonu

AU - Pers, Tune H.

AU - Farh, Kai-How

AU - Cuenca-Leon, Ester

AU - Muona, Mikko

AU - Furlotte, Nicholas A.

AU - Kurth, Tobias

AU - Ingason, Andres

AU - McMahon, George

AU - Ligthart, Lannie

AU - Terwindt, Gisela M.

AU - Kallela, Mikko

AU - Freilinger, Tobias M.

AU - Ran, Caroline

AU - Gordon, Scott G.

AU - Stam, Anine H.

AU - Steinberg, Stacy

AU - Borck, Guntram

AU - Koiranen, Markku

AU - Quaye, Lydia

AU - Adams, Hieab H. H.

AU - Lehtimaki, Terho

AU - Sarin, Antti-Pekka

AU - Wedenoja, Juho

AU - Hinds, David A.

AU - Buring, Julie E.

AU - Schurks, Markus

AU - Ridker, Paul M.

AU - Hrafnsdottir, Maria Gudlaug

AU - Stefansson, Hreinn

AU - Ring, Susan M.

AU - Hottenga, Jouke-Jan

AU - Penninx, Brenda W. J. H.

AU - Farkkila, Markus

AU - Artto, Ville

AU - Kaunisto, Mari

AU - Vepsalainen, Salli

AU - Malik, Rainer

AU - Heath, Andrew C.

AU - Madden, Pamela A. F.

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Kurki, Mitja I.

AU - Kals, Mart

AU - Magi, Reedik

AU - Parn, Kalle

AU - Hamalainen, Eija

AU - Huang, Hailiang

AU - Byrnes, Andrea E.

AU - Franke, Lude

AU - Huang, Jie

AU - Stergiakouli, Evie

AU - Lee, Phil H.

AU - Sandor, Cynthia

AU - Webber, Caleb

AU - Cader, Zameel

AU - Muller-Myhsok, Bertram

AU - Schreiber, Stefan

AU - Meitinger, Thomas

AU - Eriksson, Johan G.

AU - Salomaa, Veikko

AU - Heikkila, Kauko

AU - Loehrer, Elizabeth

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - van Duijn, Cornelia M.

AU - Cherkas, Lynn

AU - Pedersen, Linda M.

AU - Stubhaug, Audun

AU - Nielsen, Christopher S.

AU - Mannikko, Minna

AU - Mihailov, Evelin

AU - Milani, Lili

AU - Gobel, Hartmut

AU - Esserlind, Ann-Louise

AU - Christensen, Anne Francke

AU - Hansen, Thomas Folkmann

AU - Werge, Thomas

AU - Kaprio, Jaakko

AU - Aromaa, Arpo J.

AU - Raitakari, Olli

AU - Ikram, M. Arfan

AU - Spector, Tim

AU - Jarvelin, Marjo-Riitta

AU - Metspalu, Andres

AU - Kubisch, Christian

AU - Strachan, David P.

AU - Ferrari, Michel D.

AU - Belin, Andrea C.

AU - Dichgans, Martin

AU - Wessman, Maija

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

AU - Zwart, John-Anker

AU - Boomsma, Dorret I.

AU - Smith, George Davey

AU - Stefansson, Kari

AU - Eriksson, Nicholas

AU - Daly, Mark J.

AU - Neale, Benjamin M.

AU - Olesen, Jes

AU - Chasman, Daniel I.

AU - Nyholt, Dale R.

AU - Palotie, Aarno

AU - Posthuma, D

AU - Lehtimäki, T.

AU - Färkkilä, M.

AU - Vepsäläinen, S.

AU - Mägi, R.

AU - Pärn, K.

AU - Hämaläinen, E.

AU - Heikkilä, K.

AU - Loehrer, A.G.

AU - Männikkö, M.

AU - Göbel, H.

AU - Järvelin, M.R.

PY - 2016/8

Y1 - 2016/8

N2 - Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

AB - Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

U2 - https://doi.org/10.1038/ng.3598

DO - https://doi.org/10.1038/ng.3598

M3 - Article

C2 - 27322543

SN - 1061-4036

VL - 48

SP - 856

EP - 866

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -