Meta-Analysis

. 2016 Aug;48(8):856-66.

doi: 10.1038/ng.3598. Epub 2016 Jun 20.

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

Padhraig Gormley^{1

2

3

4}, Verneri Anttila^{2

3

5}, Bendik S Winsvold^{6

7

8}, Priit Palta⁹, Tonu Esko^{2

10

11}, Tune H Pers^{2

11

12

13}, Kai-How Farh^{2

5

14}, Ester Cuenca-Leon^{1

2

3

15}, Mikko Muona^{9

16

17

18}, Nicholas A Furlotte¹⁹, Tobias Kurth^{20

21}, Andres Ingason²², George McMahon²³, Lannie Ligthart²⁴, Gisela M Terwindt²⁵, Mikko Kallela²⁶, Tobias M Freilinger^{27

28}, Caroline Ran²⁹, Scott G Gordon³⁰, Anine H Stam²⁵, Stacy Steinberg²², Guntram Borck³¹, Markku Koiranen³², Lydia Quaye³³, Hieab H H Adams^{34

35}, Terho Lehtimäki³⁶, Antti-Pekka Sarin⁹, Juho Wedenoja³⁷, David A Hinds¹⁹, Julie E Buring^{21

38}, Markus Schürks³⁹, Paul M Ridker^{21

38}, Maria Gudlaug Hrafnsdottir⁴⁰, Hreinn Stefansson²², Susan M Ring²³, Jouke-Jan Hottenga²⁴, Brenda W J H Penninx⁴¹, Markus Färkkilä²⁶, Ville Artto²⁶, Mari Kaunisto⁹, Salli Vepsäläinen²⁶, Rainer Malik²⁸, Andrew C Heath⁴², Pamela A F Madden⁴², Nicholas G Martin³⁰, Grant W Montgomery³⁰, Mitja I Kurki^{1

2

3

9

43}, Mart Kals¹⁰, Reedik Mägi¹⁰, Kalle Pärn¹⁰, Eija Hämäläinen⁹, Hailiang Huang^{2

3

5}, Andrea E Byrnes^{2

3

5}, Lude Franke⁴⁴, Jie Huang⁴, Evie Stergiakouli²³, Phil H Lee^{1

2

3}, Cynthia Sandor⁴⁵, Caleb Webber⁴⁵, Zameel Cader^{46

47}, Bertram Muller-Myhsok^{48

49

50}, Stefan Schreiber⁵¹, Thomas Meitinger^{52

53}, Johan G Eriksson^{54

55}, Veikko Salomaa⁵⁵, Kauko Heikkilä⁵⁶, Elizabeth Loehrer^{34

57}, Andre G Uitterlinden⁵⁸, Albert Hofman³⁴, Cornelia M van Duijn³⁴, Lynn Cherkas³³, Linda M Pedersen⁶, Audun Stubhaug^{59

60}, Christopher S Nielsen^{59

61}, Minna Männikkö³², Evelin Mihailov¹⁰, Lili Milani¹⁰, Hartmut Göbel⁶², Ann-Louise Esserlind⁶³, Anne Francke Christensen⁶³, Thomas Folkmann Hansen⁶⁴, Thomas Werge^{65

66

67}; International Headache Genetics Consortium; Jaakko Kaprio^{9

37

68}, Arpo J Aromaa⁵⁵, Olli Raitakari^{69

70}, M Arfan Ikram^{34

35

71}, Tim Spector³³, Marjo-Riitta Järvelin^{32

72

73

74}, Andres Metspalu¹⁰, Christian Kubisch⁷⁵, David P Strachan⁷⁶, Michel D Ferrari²⁵, Andrea C Belin²⁹, Martin Dichgans^{28

49}, Maija Wessman^{9

16}, Arn M J M van den Maagdenberg^{25

77}, John-Anker Zwart^{6

7

8}, Dorret I Boomsma²⁴, George Davey Smith²³, Kari Stefansson^{22

78}, Nicholas Eriksson¹⁹, Mark J Daly^{2

3

5}, Benjamin M Neale^{2

3

5}, Jes Olesen⁶³, Daniel I Chasman^{21

38}, Dale R Nyholt⁷⁹, Aarno Palotie^{1

2

3

4

5

9

80}

Collaborators, Affiliations

Collaborators

International Headache Genetics Consortium:
Verneri Anttila, 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 M Freilinger, Nicholas A Furlotte, Padhraig Gormley, 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, Tobias Kurth, Lenore Launer, Terho Lehtimaki, Davor Lessel, Lannie Ligthart, Nadia Litterman, Arn M J M van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M Neale, Carrie Northover, Dale R Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda M Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Lydia Quaye, Olli Raitakari, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela M Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S Winsvold, William Wrenthal, Huiying Zhao, John-Anker Zwart

Affiliations

¹ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
² Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁴ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁶ FORMI, Oslo University Hospital, Oslo, Norway.
⁷ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁸ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹⁰ Estonian Genome Center, University of Tartu, Tartu, Estonia.
¹¹ Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
¹² Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
¹³ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Illumina, San Diego, California, USA.
¹⁵ Pediatric Neurology, Vall d'Hebron Research Institute, Barcelona, Spain.
¹⁶ Folkhälsan Institute of Genetics, Helsinki, Finland.
¹⁷ Neuroscience Center, University of Helsinki, Helsinki, Finland.
¹⁸ Molecular Neurology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
¹⁹ 23andMe, Inc., Mountain View, California, USA.
²⁰ Institute of Public Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
²¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
²² deCODE Genetics, Reykjavik, Iceland.
²³ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
²⁴ Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
²⁵ Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
²⁶ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
²⁷ Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
²⁸ Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
²⁹ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁰ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³¹ Institute of Human Genetics, Ulm University, Ulm, Germany.
³² Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.
³³ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
³⁴ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁵ Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁶ Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland.
³⁷ Department of Public Health, University of Helsinki, Helsinki, Finland.
³⁸ Harvard Medical School, Boston, Massachusetts, USA.
³⁹ Department of Neurology, University Duisburg-Essen, Essen, Germany.
⁴⁰ Landspitali University Hospital, Reykjavik, Iceland.
⁴¹ Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands.
⁴² Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴³ Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
⁴⁴ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁴⁵ MRC Functional Genomics Unit, Department of Physiology, Anatomy &Genetics, Oxford University, Oxford, UK.
⁴⁶ Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
⁴⁷ Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK.
⁴⁸ Max Planck Institute of Psychiatry, Munich, Germany.
⁴⁹ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁵⁰ Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
⁵¹ Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
⁵² Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
⁵³ Institute of Human Genetics, Technische Universität München, Munich, Germany.
⁵⁴ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁵⁵ National Institute for Health and Welfare, Helsinki, Finland.
⁵⁶ Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
⁵⁷ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵⁸ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵⁹ Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.
⁶⁰ Medical Faculty, University of Oslo, Oslo, Norway.
⁶¹ Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁶² Kiel Pain and Headache Center, Kiel, Germany.
⁶³ Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
⁶⁴ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark.
⁶⁵ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark.
⁶⁶ Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶⁷ iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
⁶⁸ Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
⁶⁹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁷⁰ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁷¹ Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁷² Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁷³ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁷⁴ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁷⁵ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷⁶ Population Health Research Institute, St George's, University of London, London, UK.
⁷⁷ Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
⁷⁸ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁷⁹ Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
⁸⁰ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

PMID: 27322543
PMCID: PMC5331903
DOI: 10.1038/ng.3598

Meta-Analysis

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

Padhraig Gormley et al. Nat Genet. 2016 Aug.

. 2016 Aug;48(8):856-66.

doi: 10.1038/ng.3598. Epub 2016 Jun 20.

Authors

Collaborators

International Headache Genetics Consortium:
Verneri Anttila, 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 M Freilinger, Nicholas A Furlotte, Padhraig Gormley, 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, Tobias Kurth, Lenore Launer, Terho Lehtimaki, Davor Lessel, Lannie Ligthart, Nadia Litterman, Arn M J M van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M Neale, Carrie Northover, Dale R Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda M Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Lydia Quaye, Olli Raitakari, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela M Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S Winsvold, William Wrenthal, Huiying Zhao, John-Anker Zwart

Affiliations

¹ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
² Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁴ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁶ FORMI, Oslo University Hospital, Oslo, Norway.
⁷ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁸ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹⁰ Estonian Genome Center, University of Tartu, Tartu, Estonia.
¹¹ Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
¹² Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
¹³ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Illumina, San Diego, California, USA.
¹⁵ Pediatric Neurology, Vall d'Hebron Research Institute, Barcelona, Spain.
¹⁶ Folkhälsan Institute of Genetics, Helsinki, Finland.
¹⁷ Neuroscience Center, University of Helsinki, Helsinki, Finland.
¹⁸ Molecular Neurology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
¹⁹ 23andMe, Inc., Mountain View, California, USA.
²⁰ Institute of Public Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
²¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
²² deCODE Genetics, Reykjavik, Iceland.
²³ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
²⁴ Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
²⁵ Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
²⁶ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
²⁷ Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
²⁸ Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
²⁹ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁰ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³¹ Institute of Human Genetics, Ulm University, Ulm, Germany.
³² Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland.
³³ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
³⁴ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁵ Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁶ Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland.
³⁷ Department of Public Health, University of Helsinki, Helsinki, Finland.
³⁸ Harvard Medical School, Boston, Massachusetts, USA.
³⁹ Department of Neurology, University Duisburg-Essen, Essen, Germany.
⁴⁰ Landspitali University Hospital, Reykjavik, Iceland.
⁴¹ Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands.
⁴² Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴³ Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
⁴⁴ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁴⁵ MRC Functional Genomics Unit, Department of Physiology, Anatomy &Genetics, Oxford University, Oxford, UK.
⁴⁶ Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.
⁴⁷ Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK.
⁴⁸ Max Planck Institute of Psychiatry, Munich, Germany.
⁴⁹ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁵⁰ Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
⁵¹ Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.
⁵² Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
⁵³ Institute of Human Genetics, Technische Universität München, Munich, Germany.
⁵⁴ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁵⁵ National Institute for Health and Welfare, Helsinki, Finland.
⁵⁶ Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
⁵⁷ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵⁸ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵⁹ Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway.
⁶⁰ Medical Faculty, University of Oslo, Oslo, Norway.
⁶¹ Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁶² Kiel Pain and Headache Center, Kiel, Germany.
⁶³ Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
⁶⁴ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark.
⁶⁵ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark.
⁶⁶ Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶⁷ iPSYCH-The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
⁶⁸ Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
⁶⁹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁷⁰ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁷¹ Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁷² Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁷³ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁷⁴ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁷⁵ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷⁶ Population Health Research Institute, St George's, University of London, London, UK.
⁷⁷ Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
⁷⁸ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁷⁹ Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
⁸⁰ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

PMID: 27322543
PMCID: PMC5331903
DOI: 10.1038/ng.3598

Erratum in

Corrigendum: Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.
Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH, Farh KH, 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 HH, Lehtimäki T, Sarin AP, Wedenoja J, Hinds DA, Buring JE, Schürks M, Ridker PM, Hrafnsdottir MG, Stefansson H, Ring SM, Hottenga JJ, Penninx BW, Färkkilä M, Artto V, Kaunisto M, Vepsäläinen S, Malik R, Heath AC, Madden PA, Martin NG, Montgomery GW, Kurki MI, Kals M, Mägi R, Pärn K, Hämäläinen 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, Heikkilä K, Loehrer E, Uitterlinden AG, Hofman A, van Duijn CM, Cherkas L, Pedersen LM, Stubhaug A, Nielsen CS, Männikkö M, Mihailov E, Milani L, Göbel H, Esserlind AL, Christensen AF, Hansen TF, Werge T; International Headache Genetics Consortium; Kaprio J, Aromaa AJ, Raitakari O, Ikram MA, Spector T, Järvelin MR, Metspalu A, Kubisch C, Strachan DP, Ferrari MD, Belin AC, Dichgans M, Wessman M, van den Maagdenberg AM, Zwart JA, Boomsma DI, Smith GD, Stefansson K, Eriksson… See abstract for full author list ➔ Gormley P, et al. Nat Genet. 2016 Sep 28;48(10):1296. doi: 10.1038/ng1016-1296c. Nat Genet. 2016. PMID: 27681292 No abstract available.

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.

PubMed Disclaimer

Figures

**Figure 1**
Manhattan plot of the primary meta-analysis of all migraine (59,674 cases vs. 316,078 controls). Each marker was tested for association using an additive genetic model by logistic regression adjusted for sex. A fixed-effects meta-analysis was then used to combine the association statistics from all 22 clinic and population-based studies. The horizontal axis shows the chromosomal position and the vertical axis shows the significance of tested markers from logistic regression. Markers that reach genome-wide significance (P < 5 × 10⁻⁸) at previously known and newly identified loci are highlighted according to the color legend.

**Figure 2**
Gene expression enrichment of genes from the migraine loci in GTEx tissues. Expression data from 1,641 samples was obtained using RNAseq for 42 tissues and three cell lines from the GTEx consortium. Enrichment P-values were assessed empirically for each tissue using a permutation procedure (100,000 replicates) and the red vertical line shows the significance threshold after adjusting for multiple testing by Bonferroni correction (see **Online Methods**).

**Figure 3**
Gene expression enrichment of genes from the migraine loci in 209 tissue/cell type annotations by DEPICT. Expression data was obtained from 37,427 human microarray samples and then genes in the migraine loci were assessed for high expression in each of the annotation categories. Enrichment P-values were determined by comparing the expression pattern from the migraine loci to 500 randomly generated loci and the false discovery rate (horizontal dashed line) was estimated to control for multiple testing (see **Online Methods**). A full list of these enrichment results are provided in Supplementary Table 20.

**Figure 4**
Enrichment of the migraine loci in sets of tissue-specific enhancers. We mapped credible sets from the migraine loci to sets of enhancers under active expression in 56 tissues and cell lines (identified by H3K27ac histone marks from the Roadmap Epigenomics and ENCODE projects). Enrichment P-values were assessed empirically by randomly generating a background set of matched loci for comparison (10,000 replicates) and the vertical dotted line is the significance threshold after adjusting for 56 separate tests by Bonferroni correction (see **Online Methods**).

**Figure 5**
DEPICT network of the reconstituted gene sets that were significantly enriched (false discovery rate < 0.05) for genes at the migraine loci (**Online Methods**). Enriched gene sets are represented as nodes with pairwise overlap denoted by the width of the connecting lines and empirical enrichment P-value is indicated by color intensity (darker is more significant). The 67 significantly enriched gene sets were clustered by similarity into 10 group nodes as shown in **(a)** where each group node is named after the most representative gene set in the group. **(b)** Shows one example of gene sets that were clustered within the now expanded *ITGB1* PPI group. A full list of the 67 significantly enriched reconstituted gene sets can be found in Supplementary Table 23.

See this image and copyright information in PMC

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

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

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