Abstract

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10⁻⁰⁶) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = −0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10⁻⁰⁸), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15–1.25]/10 mmHg; P = 5.57 × 10⁻²⁵) on migraine than SBP (1.05 [1.03–1.07]/10 mmHg; P = 2.60 × 10⁻⁰⁷) and a corresponding opposite effect for PP (0.92 [0.88–0.95]/10 mmHg; P = 3.65 × 10⁻⁰⁷). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.

The International Headache Genetics Consortium

Padhraig Gormley5,6,7,8, Verneri Anttila6,7,9, Bendik S. Winsvold10,11,12, Priit Palta13, Tonu Esko6,14,15, Tune H. Pers6,15,16,17, Kai-How Farh6,9,18, Ester Cuenca-Leon5,6,7,19, Mikko Muona13,20,21,22, Nicholas A. Furlotte23, Tobias Kurth24,25, Andres Ingason26, George McMahon27, Lannie Ligthart28, Gisela M. Terwindt29, Mikko Kallela30, Tobias M. Freilinger31,32, Caroline Ran33, Scott G. Gordon34, Anine H. Stam29, Stacy Steinberg26, Guntram Borck35, Markku Koiranen36, Lydia Quaye37, Hieab H. H. Adams38,39, Terho Lehtimäki40, Antti-Pekka Sarin13, Juho Wedenoja41, David A. Hinds23, Julie E. Buring25,42, Markus Schürks43, Paul M. Ridker25,42, Maria Gudlaug Hrafnsdottir44, Hreinn Stefansson26, Susan M. Ring27, Jouke-Jan Hottenga28, Brenda W. J. H. Penninx45, Markus Färkkilä30, Ville Artto30, Mari Kaunisto13, Salli Vepsäläinen30, Rainer Malik31, Andrew C. Heath46, Pamela A. F. Madden46, Nicholas G. Martin34, Grant W. Montgomery34, Mitja Kurki5,6,7, Mart Kals14, Reedik Mägi14, Kalle Pärn14, Eija Hämäläinen13, Hailiang Huang6,7,9, Andrea E. Byrnes6,7,9, Lude Franke47, Jie Huang8, Evie Stergiakouli27, Phil H. Lee5,6,7, Cynthia Sandor48, Caleb Webber48, Zameel Cader49,50, Bertram Muller-Myhsok51, Stefan Schreiber52, Thomas Meitinger53, Johan G. Eriksson54,55, Veikko Salomaa55, Kauko Heikkilä56, Elizabeth Loehrer38,57, Andre G. Uitterlinden58, Albert Hofman38, Cornelia M. van Duijn38, Lynn Cherkas37, Linda M. Pedersen10, Audun Stubhaug59,60, Christopher S. Nielsen59,61, Minna Männikkö36, Evelin Mihailov14, Lili Milani14, Hartmut Göbel62, Ann-Louise Esserlind63, Anne Francke Christensen63, Thomas Folkmann Hansen64, Thomas Werge65,66,67, Jaakko Kaprio13,68,69, Arpo J. Aromaa55, Olli Raitakari70,71, M. Arfan Ikram38,39,71,72, Tim Spector37, Marjo-Riitta Järvelin36,73,74,75, Andres Metspalu14, Christian Kubisch76, David P. Strachan77, Michel D. Ferrari29, Andrea C. Belin33, Martin Dichgans34,78, Maija Wessman13,20, Arn M. J. M. van den Maagdenberg29,79, John-Anker Zwart10,11,12, Dorret I. Boomsma28, George Davey Smith27, Kari Stefansson26,80, Nicholas Eriksson23, Mark J. Daly6,7,9, Benjamin M. Neale6,7,9, Jes Olesen63, Daniel I. Chasman25,42, Dale R. Nyholt81 & Aarno Palotie5,6,7,8,9,13,27,82

5Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 6Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 7Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 8Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. 9Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 10FORMI, Oslo University Hospital, P.O. 4956 Nydalen, 0424 Oslo, Norway. 11Department of Neurology, Oslo University Hospital, P.O. 4956 Nydalen, 0424 Oslo, Norway. 12Institute of Clinical Medicine, University of Oslo, P.O. 1171 Blindern, 0318 Oslo, Norway. 13Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 14Estonian Genome Center, University of Tartu, Tartu, Estonia. 15Division of Endocrinology, Boston Children’s Hospital, Boston, MA, USA. 16Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. 17Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. 18Illumina, Illumina Way, San Diego, CA 5200, USA. 19Vall d’Hebron Research Institute, Pediatric Neurology, Barcelona, Spain. 20Folkhälsan Institute of Genetics, FI-00290 Helsinki, Finland. 21Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland. 22Research Programs Unit, Molecular Neurology, University of Helsinki, FI-00014 Helsinki, Finland. 2323andMe, Inc., 223 N Mathilda Ave, Sunnyvale, CA 94086, USA. 24Inserm Research Center for Epidemiology and Biostatistics (U897), University of Bordeaux, 33076 Bordeaux, France. 25Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA. 26deCODE Genetics, 101 Reykjavik, Iceland. 27Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK. 28Department of Biological Psychology, VU University Amsterdam, 1081 BT Amsterdam, The Netherlands. 29Department of Neurology, Leiden University Medical Centre, PO Box 96002300 RC Leiden, The Netherlands. 30Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland. 31Institute for Stroke and Dementia Research, Klinikum der Universtität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, 81377 Munich, Germany. 32Department of Neurology and Epileptology, Hertie Institute for Clincal Brain Research, University of Tuebingen, Tuebingen, Germany. 33Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. 34Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia. 35Institute of Human Genetics, Ulm University, 89081 Ulm, Germany. 36Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Box 5000FI-90014 Oulu, Finland. 37Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. 38Department of Epidemiology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands. 39Department of Radiology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands. 40Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, 33520 Tampere, Finland. 41Department of Public Health, University of Helsinki, Helsinki, Finland. 42Harvard Medical School, Boston, MA 02115, USA. 43University Duisburg Essen, Essen, Germany. 44Landspitali University Hospital, 101 Reykjavik, Iceland. 45Department of Psychiatry, VU University Medical Centre, 1081 HL Amsterdam, The Netherlands. 46Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, CB 8134, St. Louis, MO 63110, USA. 47University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 9700RB. 48MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, UK. 49Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK. 50Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK. 51Max-Planck-Institute of Psychiatry, Munich, Germany. 52Christian Albrechts University, Kiel, Germany. 53Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany. 54Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 55National Institute for Health and Welfare, Helsinki, Finland. 56Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland. 57Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. 58Department of Internal Medicine, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands. 59Department of Pain Management and Research, Oslo University Hospital, 0424 Oslo, Norway. 60Medical Faculty, University of Oslo, 0318 Oslo, Norway. 61Division of Mental Health, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen0403 Oslo, Norway. 62Kiel Pain and Headache Center, 24149 Kiel, Germany. 63Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark. 64Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark. 65Institute Of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, 2100 Copenhagen, Denmark. 66Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, 2100 Copenhagen, Denmark. 67iPSYCH - The Lundbeck Foundation’s Initiative for Integrative Psychiatric Research, 2100 Copenhagen, Denmark. 68Department of Public Health, University of Helsinki, Helsinki, Finland. 69Department of Health, National Institute for Health and Welfare, Helsinki, Finland. 70Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20521 Turku, Finland. 71Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20521 Turku, Finland. 72Department of Neurology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands. 73Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. 74Biocenter Oulu, University of Oulu, Box 500090014 Oulu, Finland. 75Unit of Primary Care, Oulu University Hospital, Box 10FIN-90029 Oulu, Finland. 76University Medical Center Hamburg Eppendorf, Institute of Human Genetics, 20246 Hamburg, Germany. 77Population Health Research Institute, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK. 78Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 79Leiden University Medical Centre, Department of Human Genetics, PO Box 96002300 RC Leiden, The Netherlands. 80Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. 81Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia. 82Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

The 23andMe Research Team

Michelle Agee83, Adam Auton83, Robert K. Bell83, Katarzyna Bryc83, Sarah L. Elson83, Pierre Fontanillas83, Nicholas A. Furlotte83, David A. Hinds83, Karen E. Huber83, Aaron Kleinman83, Nadia K. Litterman83, Jennifer C. McCreight83, Matthew H. McIntyre83, Joanna L. Mountain83, Elizabeth S. Noblin83, Carrie A. M. Northover83, Steven J. Pitts83, J. Fah Sathirapongsasuti83, Olga V. Sazonova83, Janie F. Shelton83, Suyash Shringarpure83, Chao Tian83, Joyce Y. Tung83 & Vladimir Vacic83

8323andMe, Inc., 223 N Mathilda Ave, Sunnyvale, CA 94086, USA.