Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache

doi:10.1093/ije/dyaa050

. 2020 Jun 1;49(3):1022-1031.

doi: 10.1093/ije/dyaa050.

Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache

Katherine M Siewert¹, Derek Klarin^{2

3

4}, Scott M Damrauer^{5

6}, Kyong-Mi Chang^{5

7}, Philip S Tsao^{8

9}, Themistocles L Assimes^{8

9}, George Davey Smith^{10

11}, Benjamin F Voight^{5

12

13

14}; The International Headache Genetics Consortium

Collaborators, Affiliations

Collaborators

The International Headache Genetics Consortium:
Padhraig Gormley^{15

16

17

18}, Verneri Anttila^{16

17

19

20}, Bendik S Winsvold^{20

21

22}, Priit Palta²³, Tonu Esko^{16

24

25}, Tune H. Pers^{16

25

26

27}, Kai-How Farh^{16

19

28}, Ester Cuenca-Leon^{15

16

17

29}, Mikko Muona^{23

30

31

32}, Nicholas A Furlotte³³, Tobias Kurth^{34

35}, Andres Ingason³⁶, George McMahon³⁷, Lannie Ligthart³⁸, Gisela M Terwindt³⁹, Mikko Kallela⁴⁰, Tobias M Freilinger^{41

42}, Caroline Ran⁴³, Scott G Gordon⁴⁴, Anine H Stam³⁹, Stacy Steinberg³⁶, Guntram Borck⁴⁵, Markku Koiranen⁴⁶, Lydia Quaye⁴⁷, Hieab HH Adams^{48

49}, Terho Lehtimäki⁵⁰, Antti-Pekka Sarin²³, Juho Wedenoja⁵¹, David A Hinds³³, Julie E Buring^{35

52}, Markus Schürks⁵³, Paul M Ridker^{35

52}, Maria Gudlaug Hrafnsdottir⁵⁴, Hreinn Stefansson³⁶, Susan M Ring³⁷, Jouke-Jan Hottenga³⁸, Brenda WJH Penninx⁵⁵, Markus Färkkilä⁴⁰, Ville Artto⁴⁰, Mari Kaunisto²³, Salli Vepsäläinen⁴⁰, Rainer Malik⁴¹, Andrew C Heath⁵⁶, Pamela A F Madden⁵⁶, Nicholas G Martin⁴⁴, Grant W Montgomery⁴⁴, Mitja Kurki^{15

16

17}, Mart Kals²⁴, Reedik Mägi²⁴, Kalle Pärn²⁴, Eija Hämäläinen²³, Hailiang Huang^{16

17

19}, Andrea E Byrnes^{16

17

19}, Lude Franke⁵⁷, Jie Huang¹⁸, Evie Stergiakouli³⁷, Phil H Lee^{15

16

17}, Cynthia Sandor⁵⁸, Caleb Webber⁵⁸, Zameel Cader^{59

60}, Bertram Muller-Myhsok⁶¹, Stefan Schreiber⁶², Thomas Meitinger⁶³, Johan G Eriksson^{64

65}, Veikko Salomaa⁶⁵, Kauko Heikkilä⁶⁶, Elizabeth Loehrer^{48

67}, Andre G Uitterlinden⁶⁸, Albert Hofman⁴⁸, Cornelia M van Duijn⁴⁸, Lynn Cherkas⁴⁷, Linda M. Pedersen²⁰, Audun Stubhaug^{69

70}, Christopher S Nielsen^{69

71}, Minna Männikkö⁴⁶, Evelin Mihailov²⁴, Lili Milani²⁴, Hartmut Göbel⁷², Ann-Louise Esserlind⁷³, Anne Francke Christensen⁷³, Thomas Folkmann Hansen⁷⁴, Thomas Werge^{75

76

77}, Sigrid Børte⁷⁸, Bru Cormand⁷⁹, Else Eising⁸⁰, Lyn Griffiths⁸¹, Eija Hamalainen²³, Marjo Hiekkala³⁰, Risto Kajanne²³, Lenore Launer⁸², Terho Lehtimaki⁸³, Davor Leslsel⁸⁴, Alfons Macaya²⁹, Massimo Mangino⁴⁷, Nancy Pedersen⁸⁵, Danielle Posthuma⁸⁶, Patricia Pozo-Rosich⁸⁷, Alice Pressman⁸⁸, Celia Sintas⁷⁹, Marta Vila-Pueyo²⁹, Huiying Zhao⁸², Jaakko Kaprio^{23

89

90}, Arpo J Aromaa⁶⁵, Olli Raitakari^{91

92}, M Arfan Ikram^{48

49

92}, Tim Spector⁴⁷, Marjo-Riitta Järvelin^{46

93

94

95}, Andres Metspalu²⁴, Christian Kubisch⁹⁶, David P Strachan⁹⁷, Michel D Ferrari³⁹, Andrea C Belin⁴³, Martin Dichgans^{41

98}, Maija Wessman^{23

30}, Arn MJM van den Maagdenberg^{39

99}, John-Anker Zwart^{20

21

22}, Dorret I Boomsma³⁸, George Davey Smith³⁷, Kari Stefansson^{36

100}, Nicholas Eriksson³³, Mark J Daly^{16

17

19}, Benjamin M Neale^{16

17

19}, Jes Olesen⁷³, Daniel I Chasman^{35

53}, Dale R Nyholt¹⁰¹, Aarno Palotie^{15

16

17

18

19

23

102}

Affiliations

¹ Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Boston VA Healthcare System, Boston, MA, USA.
⁵ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁶ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁰ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹¹ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
¹² Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA
¹⁶ Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, USA
¹⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA
¹⁸ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
¹⁹ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA
²⁰ FORMI, Oslo University Hospital, P.O. 4956 Nydalen, 0424 Oslo, Norway
²¹ Department of Neurology, Oslo University Hospital, P.O. 4956 Nydalen, 0424 Oslo, Norway
²² Institute of Clinical Medicine, University of Oslo, P.O. 1171 Blindern, 0318 Oslo, Norway
²³ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
²⁴ Estonian Genome Center, University of Tartu, Tartu, Estonia
²⁵ Division of Endocrinology, Boston Children's Hospital, Boston, USA
²⁶ Statens Serum Institut, Dept of Epidemiology Research, Copenhagen, Denmark
²⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
²⁸ Illumina, 5200 Illumina Way, San Diego, USA
²⁹ Vall d'Hebron Research Institute, Pediatric Neurology, Barcelona, Spain
³⁰ Folkhälsan Institute of Genetics, Helsinki, Finland, FI-00290
³¹ Neuroscience Center, University of Helsinki, Helsinki, Finland, FI-00014
³² Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland, FI-00014
³³ 23andMe, Inc., 899 W. Evelyn Avenue, Mountain View, CA, USA
³⁴ Inserm Research Center for Epidemiology and Biostatistics (U897), University of Bordeaux, 33076 Bordeaux, France
³⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA 02215
³⁶ deCODE Genetics, 101 Reykjavik, Iceland
³⁷ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK
³⁸ VU University Amsterdam, Department of Biological Psychology, Amsterdam, the Netherlands, 1081 BT
³⁹ Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, PO Box 9600, 2300 RC
⁴⁰ Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
⁴¹ Institute for Stroke and Dementia Research, Klinikum der Universtität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, 81377 Munich Germany
⁴² Department of Neurology and Epileptology, Hertie Institute for Clincal Brain Research, University of Tuebingen
⁴³ Karolinska Institutet, Department of Neuroscience, 171 77 Stockholm, Sweden
⁴⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
⁴⁵ Ulm University, Institute of Human Genetics, 89081 Ulm, Germany
⁴⁶ University of Oulu, Center for Life Course Epidemiology and Systems Medicine, Oulu, Finland, Box 5000, Fin-90014 University of Oulu
⁴⁷ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
⁴⁸ Dept of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands, 3015 CN
⁴⁹ Dept of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands, 3015 CN
⁵⁰ Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Tampere, Finland, 33520
⁵¹ Department of Public Health, University of Helsinki, Helsinki, Finland
⁵² Harvard Medical School, Boston MA 02115
⁵³ University Duisburg Essen, Essen, Germany
⁵⁴ Landspitali University Hospital, 101 Reykjavik, Iceland
⁵⁵ VU University Medical Centre, Department of Psychiatry, Amsterdam, the Netherlands, 1081 HL
⁵⁶ Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, CB 8134, St. Louis, MO 63110, USA
⁵⁷ University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 9700RB
⁵⁸ MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, Oxford University, UK
⁵⁹ Nuffield Department of Clinical Neuroscience, University of Oxford, UK
⁶⁰ Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK
⁶¹ Max-Planck-Institute of Psychiatry, Munich, Germany
⁶² Christian Albrechts University, Kiel, Germany
⁶³ Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
⁶⁴ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki Finland
⁶⁵ National Institute for Health and Welfare, Helsinki, Finland
⁶⁶ Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
⁶⁷ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, USA 02115
⁶⁸ Dept of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands, 3015 CN
⁶⁹ Dept of Pain Management and Research, Oslo University Hospital, Oslo, 0424 Oslo, Norway
⁷⁰ Medical Faculty, University of Oslo, Oslo, 0318 Oslo, Norway
⁷¹ Division of Mental Health, Norwegian Institute of Public Health,P.O. Box 4404 Nydalen, Oslo, Norway, NO-0403
⁷² Kiel Pain and Headache Center, 24149 Kiel, Germany
⁷³ Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Denmark
⁷⁴ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark
⁷⁵ Institute Of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, DK-2100 Copenhagen, Denmark
⁷⁶ Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
⁷⁷ iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark
⁷⁸ Oslo University Hospital and University of Oslo, Oslo, Norway
⁷⁹ University of Barcelona, Barcelona, Spain
⁸⁰ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, 6525 XD, The Netherlands
⁸¹ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
⁸² National Institute on Aging, Bethesda, USA
⁸³ School of Medicine, University of Tampere, Kalevantie
⁸⁴ University Medical Center Hamburg-Eppendorf, Hamburg, Germany
⁸⁵ Karolinska Institutet, Stockholm, Sweden
⁸⁶ VU University, Amsterdam, The Netherlands
⁸⁷ Universitat Autònoma de Barcelona, Barcelona, Spain
⁸⁸ Sutter Health, Sacramento, USA
⁸⁹ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁹⁰ Department of Health, National Institute for Health and Welfare, Helsinki, Finland
⁹¹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland, 20521
⁹² Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland, 20521
⁹³ Imperial College London, Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, UK, W2 1PG
⁹⁴ University of Oulu, Biocenter Oulu, Finland, Box 5000, Fin-90014 University of Oulu
⁹⁵ Oulu University Hospital, Unit of Primary Care, Oulu, Finland, Box 10, Fin-90029 OYS
⁹⁶ University Medical Center Hamburg Eppendorf, Institute of Human Genetics, 20246 Hamburg, Germany
⁹⁷ Population Health Research Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK
⁹⁸ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
⁹⁹ Leiden University Medical Centre, Department of Human Genetics, Leiden, The Netherlands, PO Box 9600, 2300 RC
¹⁰⁰ Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
¹⁰¹ Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia
¹⁰² Department of Neurology, Massachusetts General Hospital, Boston, USA

PMID: 32306029
PMCID: PMC7394956
DOI: 10.1093/ije/dyaa050

Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache

Katherine M Siewert et al. Int J Epidemiol. 2020.

. 2020 Jun 1;49(3):1022-1031.

doi: 10.1093/ije/dyaa050.

Authors

Collaborators

The International Headache Genetics Consortium:
Padhraig Gormley^{15

16

17

18}, Verneri Anttila^{16

17

19

20}, Bendik S Winsvold^{20

21

22}, Priit Palta²³, Tonu Esko^{16

24

25}, Tune H. Pers^{16

25

26

27}, Kai-How Farh^{16

19

28}, Ester Cuenca-Leon^{15

16

17

29}, Mikko Muona^{23

30

31

32}, Nicholas A Furlotte³³, Tobias Kurth^{34

35}, Andres Ingason³⁶, George McMahon³⁷, Lannie Ligthart³⁸, Gisela M Terwindt³⁹, Mikko Kallela⁴⁰, Tobias M Freilinger^{41

42}, Caroline Ran⁴³, Scott G Gordon⁴⁴, Anine H Stam³⁹, Stacy Steinberg³⁶, Guntram Borck⁴⁵, Markku Koiranen⁴⁶, Lydia Quaye⁴⁷, Hieab HH Adams^{48

49}, Terho Lehtimäki⁵⁰, Antti-Pekka Sarin²³, Juho Wedenoja⁵¹, David A Hinds³³, Julie E Buring^{35

52}, Markus Schürks⁵³, Paul M Ridker^{35

52}, Maria Gudlaug Hrafnsdottir⁵⁴, Hreinn Stefansson³⁶, Susan M Ring³⁷, Jouke-Jan Hottenga³⁸, Brenda WJH Penninx⁵⁵, Markus Färkkilä⁴⁰, Ville Artto⁴⁰, Mari Kaunisto²³, Salli Vepsäläinen⁴⁰, Rainer Malik⁴¹, Andrew C Heath⁵⁶, Pamela A F Madden⁵⁶, Nicholas G Martin⁴⁴, Grant W Montgomery⁴⁴, Mitja Kurki^{15

16

17}, Mart Kals²⁴, Reedik Mägi²⁴, Kalle Pärn²⁴, Eija Hämäläinen²³, Hailiang Huang^{16

17

19}, Andrea E Byrnes^{16

17

19}, Lude Franke⁵⁷, Jie Huang¹⁸, Evie Stergiakouli³⁷, Phil H Lee^{15

16

17}, Cynthia Sandor⁵⁸, Caleb Webber⁵⁸, Zameel Cader^{59

60}, Bertram Muller-Myhsok⁶¹, Stefan Schreiber⁶², Thomas Meitinger⁶³, Johan G Eriksson^{64

65}, Veikko Salomaa⁶⁵, Kauko Heikkilä⁶⁶, Elizabeth Loehrer^{48

67}, Andre G Uitterlinden⁶⁸, Albert Hofman⁴⁸, Cornelia M van Duijn⁴⁸, Lynn Cherkas⁴⁷, Linda M. Pedersen²⁰, Audun Stubhaug^{69

70}, Christopher S Nielsen^{69

71}, Minna Männikkö⁴⁶, Evelin Mihailov²⁴, Lili Milani²⁴, Hartmut Göbel⁷², Ann-Louise Esserlind⁷³, Anne Francke Christensen⁷³, Thomas Folkmann Hansen⁷⁴, Thomas Werge^{75

76

77}, Sigrid Børte⁷⁸, Bru Cormand⁷⁹, Else Eising⁸⁰, Lyn Griffiths⁸¹, Eija Hamalainen²³, Marjo Hiekkala³⁰, Risto Kajanne²³, Lenore Launer⁸², Terho Lehtimaki⁸³, Davor Leslsel⁸⁴, Alfons Macaya²⁹, Massimo Mangino⁴⁷, Nancy Pedersen⁸⁵, Danielle Posthuma⁸⁶, Patricia Pozo-Rosich⁸⁷, Alice Pressman⁸⁸, Celia Sintas⁷⁹, Marta Vila-Pueyo²⁹, Huiying Zhao⁸², Jaakko Kaprio^{23

89

90}, Arpo J Aromaa⁶⁵, Olli Raitakari^{91

92}, M Arfan Ikram^{48

49

92}, Tim Spector⁴⁷, Marjo-Riitta Järvelin^{46

93

94

95}, Andres Metspalu²⁴, Christian Kubisch⁹⁶, David P Strachan⁹⁷, Michel D Ferrari³⁹, Andrea C Belin⁴³, Martin Dichgans^{41

98}, Maija Wessman^{23

30}, Arn MJM van den Maagdenberg^{39

99}, John-Anker Zwart^{20

21

22}, Dorret I Boomsma³⁸, George Davey Smith³⁷, Kari Stefansson^{36

100}, Nicholas Eriksson³³, Mark J Daly^{16

17

19}, Benjamin M Neale^{16

17

19}, Jes Olesen⁷³, Daniel I Chasman^{35

53}, Dale R Nyholt¹⁰¹, Aarno Palotie^{15

16

17

18

19

23

102}

Affiliations

¹ Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Boston VA Healthcare System, Boston, MA, USA.
⁵ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁶ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁰ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹¹ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
¹² Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA
¹⁶ Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, USA
¹⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA
¹⁸ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
¹⁹ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA
²⁰ FORMI, Oslo University Hospital, P.O. 4956 Nydalen, 0424 Oslo, Norway
²¹ Department of Neurology, Oslo University Hospital, P.O. 4956 Nydalen, 0424 Oslo, Norway
²² Institute of Clinical Medicine, University of Oslo, P.O. 1171 Blindern, 0318 Oslo, Norway
²³ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
²⁴ Estonian Genome Center, University of Tartu, Tartu, Estonia
²⁵ Division of Endocrinology, Boston Children's Hospital, Boston, USA
²⁶ Statens Serum Institut, Dept of Epidemiology Research, Copenhagen, Denmark
²⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
²⁸ Illumina, 5200 Illumina Way, San Diego, USA
²⁹ Vall d'Hebron Research Institute, Pediatric Neurology, Barcelona, Spain
³⁰ Folkhälsan Institute of Genetics, Helsinki, Finland, FI-00290
³¹ Neuroscience Center, University of Helsinki, Helsinki, Finland, FI-00014
³² Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland, FI-00014
³³ 23andMe, Inc., 899 W. Evelyn Avenue, Mountain View, CA, USA
³⁴ Inserm Research Center for Epidemiology and Biostatistics (U897), University of Bordeaux, 33076 Bordeaux, France
³⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA 02215
³⁶ deCODE Genetics, 101 Reykjavik, Iceland
³⁷ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK
³⁸ VU University Amsterdam, Department of Biological Psychology, Amsterdam, the Netherlands, 1081 BT
³⁹ Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, PO Box 9600, 2300 RC
⁴⁰ Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
⁴¹ Institute for Stroke and Dementia Research, Klinikum der Universtität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, 81377 Munich Germany
⁴² Department of Neurology and Epileptology, Hertie Institute for Clincal Brain Research, University of Tuebingen
⁴³ Karolinska Institutet, Department of Neuroscience, 171 77 Stockholm, Sweden
⁴⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
⁴⁵ Ulm University, Institute of Human Genetics, 89081 Ulm, Germany
⁴⁶ University of Oulu, Center for Life Course Epidemiology and Systems Medicine, Oulu, Finland, Box 5000, Fin-90014 University of Oulu
⁴⁷ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
⁴⁸ Dept of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands, 3015 CN
⁴⁹ Dept of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands, 3015 CN
⁵⁰ Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Tampere, Finland, 33520
⁵¹ Department of Public Health, University of Helsinki, Helsinki, Finland
⁵² Harvard Medical School, Boston MA 02115
⁵³ University Duisburg Essen, Essen, Germany
⁵⁴ Landspitali University Hospital, 101 Reykjavik, Iceland
⁵⁵ VU University Medical Centre, Department of Psychiatry, Amsterdam, the Netherlands, 1081 HL
⁵⁶ Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, CB 8134, St. Louis, MO 63110, USA
⁵⁷ University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 9700RB
⁵⁸ MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, Oxford University, UK
⁵⁹ Nuffield Department of Clinical Neuroscience, University of Oxford, UK
⁶⁰ Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK
⁶¹ Max-Planck-Institute of Psychiatry, Munich, Germany
⁶² Christian Albrechts University, Kiel, Germany
⁶³ Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
⁶⁴ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki Finland
⁶⁵ National Institute for Health and Welfare, Helsinki, Finland
⁶⁶ Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
⁶⁷ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, USA 02115
⁶⁸ Dept of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands, 3015 CN
⁶⁹ Dept of Pain Management and Research, Oslo University Hospital, Oslo, 0424 Oslo, Norway
⁷⁰ Medical Faculty, University of Oslo, Oslo, 0318 Oslo, Norway
⁷¹ Division of Mental Health, Norwegian Institute of Public Health,P.O. Box 4404 Nydalen, Oslo, Norway, NO-0403
⁷² Kiel Pain and Headache Center, 24149 Kiel, Germany
⁷³ Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Denmark
⁷⁴ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark
⁷⁵ Institute Of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, DK-2100 Copenhagen, Denmark
⁷⁶ Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
⁷⁷ iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark
⁷⁸ Oslo University Hospital and University of Oslo, Oslo, Norway
⁷⁹ University of Barcelona, Barcelona, Spain
⁸⁰ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, 6525 XD, The Netherlands
⁸¹ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
⁸² National Institute on Aging, Bethesda, USA
⁸³ School of Medicine, University of Tampere, Kalevantie
⁸⁴ University Medical Center Hamburg-Eppendorf, Hamburg, Germany
⁸⁵ Karolinska Institutet, Stockholm, Sweden
⁸⁶ VU University, Amsterdam, The Netherlands
⁸⁷ Universitat Autònoma de Barcelona, Barcelona, Spain
⁸⁸ Sutter Health, Sacramento, USA
⁸⁹ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁹⁰ Department of Health, National Institute for Health and Welfare, Helsinki, Finland
⁹¹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland, 20521
⁹² Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland, 20521
⁹³ Imperial College London, Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, UK, W2 1PG
⁹⁴ University of Oulu, Biocenter Oulu, Finland, Box 5000, Fin-90014 University of Oulu
⁹⁵ Oulu University Hospital, Unit of Primary Care, Oulu, Finland, Box 10, Fin-90029 OYS
⁹⁶ University Medical Center Hamburg Eppendorf, Institute of Human Genetics, 20246 Hamburg, Germany
⁹⁷ Population Health Research Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK
⁹⁸ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
⁹⁹ Leiden University Medical Centre, Department of Human Genetics, Leiden, The Netherlands, PO Box 9600, 2300 RC
¹⁰⁰ Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
¹⁰¹ Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia
¹⁰² Department of Neurology, Massachusetts General Hospital, Boston, USA

PMID: 32306029
PMCID: PMC7394956
DOI: 10.1093/ije/dyaa050

Erratum in

Erratum to: Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache.
Siewert KM, Klarin D, Damrauer SM, Chang KM, Tsao PS, Assimes TL, Smith GD, Voight BF. Siewert KM, et al. Int J Epidemiol. 2020 Oct 1;49(5):1759. doi: 10.1093/ije/dyaa154. Int J Epidemiol. 2020. PMID: 33280006 Free PMC article. No abstract available.

Abstract

Background: Nearly a fifth of the world's population suffer from migraine headache, yet risk factors for this disease are poorly characterized.

Methods: To further elucidate these factors, we conducted a genetic correlation analysis using cross-trait linkage disequilibrium (LD) score regression between migraine headache and 47 traits from the UK Biobank. We then tested for possible causality between these phenotypes and migraine, using Mendelian randomization. In addition, we attempted replication of our findings in an independent genome-wide association study (GWAS) when available.

Results: We report multiple phenotypes with genetic correlation (P < 1.06 × 10-3) with migraine, including heart disease, type 2 diabetes, lipid levels, blood pressure, autoimmune and psychiatric phenotypes. In particular, we find evidence that blood pressure directly contributes to migraine and explains a previously suggested causal relationship between calcium and migraine.

Conclusions: This is the largest genetic correlation analysis of migraine headache to date, both in terms of migraine GWAS sample size and the number of phenotypes tested. We find that migraine has a shared genetic basis with a large number of traits, indicating pervasive pleiotropy at migraine-associated loci.

Keywords: Genetic correlation; Mendelian randomization; headache; migraine.

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Figures

**Figure 1**
Cross-trait linkage disequilibrium score regression results between migraine and 47 different phenotypes from the UK Biobank. Numbers correspond to the strength of genetic correlation, and asterisks represent P-values of these associations. BMI, body mass index; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; ENT, ear, nose and throat disorders.

**Figure 2**
Genetic correlation of lipid traits with migraine headache and migraine subtypes using cross-trait linkage disequilibrium score regression. Error bars represent the 95% confidence interval. Lipid genome-wide association study is from Klarin (2018). HDL, high-density lipoprotein; LDL, low-density lipoprotein.

**Figure 3**
Effect of diastolic blood pressure and calcium on migraine-all. ‘Single trait’ is the estimated effect of the given biomarker on migraine-all using Mendelian randomization of only the given biomarker. “Multi-trait” is the estimated effect of the biomarker on migraine-all using the residual of the outcome after adjustment for the other biomarker. Error bars represent the 95% confidence interval.

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References

1. Vos T, Barber RM, Bell B et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;386:743–800. - PMC - PubMed
1. Burch R, Rayhill M. New preventive treatments for migraine. BMJ 2018;361:k2507. - PubMed
1. Gustavsson A, Svensson M, Jacobi F et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:718–79. - PubMed
1. Polderman TJC, Benyamin B, Leeuw CD et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 2015;47:702–09. - PubMed
1. Gormley P, Anttila V, Winsvold BS et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 2016;48:856–66. - PMC - PubMed

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[1] Vos T, Barber RM, Bell B et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;386:743–800. - PMC - PubMed

[2] Vos T, Barber RM, Bell B et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;386:743–800. - PMC - PubMed

[3] Burch R, Rayhill M. New preventive treatments for migraine. BMJ 2018;361:k2507. - PubMed

[4] Burch R, Rayhill M. New preventive treatments for migraine. BMJ 2018;361:k2507. - PubMed

[5] Gustavsson A, Svensson M, Jacobi F et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:718–79. - PubMed

[6] Gustavsson A, Svensson M, Jacobi F et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:718–79. - PubMed

[7] Polderman TJC, Benyamin B, Leeuw CD et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 2015;47:702–09. - PubMed

[8] Polderman TJC, Benyamin B, Leeuw CD et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 2015;47:702–09. - PubMed

[9] Gormley P, Anttila V, Winsvold BS et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 2016;48:856–66. - PMC - PubMed

[10] Gormley P, Anttila V, Winsvold BS et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 2016;48:856–66. - PMC - PubMed

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Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache

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Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache

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