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Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants. Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. Eating Disorders Working Group of the Psychiatric Genomics Consortium Roger Adan17,18,19, Lars Alfredsson20, Tetsuya Ando21, Ole Andreassen22, Jessica Baker9, Andrew Bergen23,24, Wade Berrettini25, Andreas Birgegård26,27, Joseph Boden28, Ilka Boehm29, Claudette Boni30, Vesna Boraska Perica31,32, Harry Brandt33, Gerome Breen13,14, Julien Bryois1, Katharina Buehren34, Cynthia Bulik1,9,15, Roland Burghardt35, Matteo Cassina36, Sven Cichon37, Maurizio Clementi36, Jonathan Coleman13,14, Roger Cone38, Philippe Courtet39, Steven Crawford33, Scott Crow40, James Crowley16,26, unna Danner18, Oliver Davis41,42, Martina de Zwaan43, George Dedoussis44, Daniela Degortes45, Janiece DeSocio46, Danielle Dick47, Dimitris Dikeos48, Christian Dina49,50, Monika Dmitrzak-Weglarz51, Elisa Docampo Martinez52,53,54, Laramie Duncan55, Karin Egberts56, Stefan Ehrlich29, Geòrgia Escaramís52,53,54, Tõnu Esko57,58, Xavier Estivill52,53,54,59, Anne Farmer13, Angela Favaro45, Fernando Fernández-Aranda60,61, Manfred Fichter62,63, Krista Fischer57, Manuel Föcker64, Lenka Foretova65, Andreas Forstner37,66,67,68,69, Monica Forzan36, Christopher Franklin31, Steven Gallinger70, Héléna Gaspar13,14, Ina Giegling71, Johanna Giuranna64, Paola Giusti-Rodríquez16, Fragiskos Gonidakis72, Scott Gordon73, Philip Gorwood30,74, Monica Gratacos Mayora52,53,54, Jakob Grove75,76,77,78, Sébastien Guillaume39, Yiran Guo79, Hakon Hakonarson79,80, Katherine Halmi81, Ken Hanscombe82, Konstantinos Hatzikotoulas31, Joanna Hauser83, Johannes Hebebrand64, Sietske Helder13,84, Anjali Henders85, Stefan Herms37,69, Beate Herpertz-Dahlmann34, Wolfgang Herzog86, Anke Hinney64, L. John Horwood28, Christopher Hübel1,13, Laura Huckins31,87, James Hudson88, Hartmut Imgart89, Hidetoshi Inoko90, Vladimir Janout91, Susana Jiménez-Murcia60,61, Craig Johnson92, Jennifer Jordan93,94, Antonio Julià95, Anders Juréus1, Gursharan Kalsi13, Deborah Kaminská96, Allan Kaplan97, Jaakko Kaprio98,99, Leila Karhunen100, Andreas Karwautz101, Martien Kas17,102, Walter Kaye103, James Kennedy97, Martin Kennedy104, Anna Keski-Rahkonen98, Kirsty Kiezebrink105, Youl-Ri Kim106, Katherine Kirk73, Lars Klareskog107, Kelly Klump108, Gun Peggy Knudsen109, Maria La Via9, Mikael Landén1,19, Janne Larsen76,110,111, Stephanie Le Hellard112,113,114, Virpi Leppä1, Robert Levitan115, Dong Li79, Paul Lichtenstein1, Lisa Lilenfeld116, Bochao Danae Lin17, Jolanta Lissowska117, Jurjen Luykx17, Pierre Magistretti118,119, Mario Maj120, Katrin Mannik57,121, Sara Marsal95, Christian Marshall122, Nicholas Martin73, Manuel Mattheisen26,27,75,123, Morten Mattingsdal22, Sara McDevitt124,125, Peter McGuffin13, Sarah Medland73, Andres Metspalu57,126, Ingrid Meulenbelt127, Nadia Micali128,129, James Mitchell130, Karen Mitchell131, Palmiero Monteleone132, Alessio Maria Monteleone120, Grant Montgomery73,85,133, Preben Bo Mortensen76,110,111, Melissa Munn-Chernoff9, Benedetta Nacmias134, Marie Navratilova65, Claes Norring26,27, Ioanna Ntalla44, Catherine Olsen73, Roel Ophoff17,135, Julie O’Toole136, Leonid Padyukov107, Aarno Palotie58,99,137, Jacques Pantel30, Hana Papezova96, Richard Parker73, John Pearson138, Nancy Pedersen1, Liselotte Petersen76,110,111, Dalila Pinto87, Kirstin Purves13, Raquel Rabionet139,140,141, Anu Raevuori98, Nicolas Ramoz30, Ted Reichborn-Kjennerud109,142, Valdo Ricca134,143, Samuli Ripatti144, Stephan Ripke145,146,147, Franziska Ritschel29,148, Marion Roberts13, Alessandro Rotondo149, Dan Rujescu62,71, Filip Rybakowski150, Paolo Santonastaso151, André Scherag152, Stephen Scherer153, ulrike Schmidt13, Nicholas Schork154, Alexandra Schosser155, Jochen Seitz34, Lenka Slachtova156, P. Eline Slagboom127, Margarita Slof-Op ‘t Landt157,158, Agnieszka Slopien159, Sandro Sorbi134,160, Michael Strober161,162, Garret Stuber9,163, Patrick Sullivan1,16, Beata Świątkowska164, Jin Szatkiewicz16, Ioanna Tachmazidou31, Elena Tenconi45, Laura Thornton9, Alfonso Tortorella165,166, Federica Tozzi167, Janet Treasure13, Artemis Tsitsika168, Marta Tyszkiewicz-Nwafor150, Konstantinos Tziouvas169, Annemarie van Elburg18,170, Eric van Furth157,158, Tracey Wade171, Gudrun Wagner101, Esther Walton29, Hunna Watson9,10,11, Thomas Werge172, David Whiteman73, Elisabeth Widen99, D. Blake Woodside173,174, Shuyang Yao1, Zeynep Yilmaz9,16, Eleftheria Zeggini31,175, Stephanie Zerwas9 and Stephan Zipfel176 17Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. 18Center for Eating Disorders Rintveld, Altrecht Mental Health Institute, Zeist, the Netherlands. 19Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 20Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 21Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan. 22NORMENT KG Jebsen Centre, Division of Mental Health and Addiction, University of Oslo, Oslo University Hospital, Oslo, Norway. 23BioRealm, LLC, Walnut, CA, USA. 24Oregon Research Institute, Eugene, OR, USA. 25Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. 26Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 27Center for Psychiatry Research, Stockholm Health Care Services, Stockholm City Council, Stockholm, Sweden. 28Christchurch Health and Development Study, University of Otago, Christchurch, New Zealand. 29Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. 30INSERM U894, Centre of Psychiatry and Neuroscience, Paris, France. 31Wellcome Sanger Institute, Hinxton, Cambridge, UK. 32Department of Medical Biology, School of Medicine, University of Split, Split, Croatia. 33The Center for Eating Disorders at Sheppard Pratt, Baltimore, MD, USA. 34Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany. 35Klinikum Frankfurt/Oder, Frankfurt, Germany. 36Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padua, Italy. 37Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. 38Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. 39Department of Emergency Psychiatry and Post-Acute Care, CHRU Montpellier, University of Montpellier, Montpellier, France. 40Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA. 41MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. 42School of Social and Community Medicine, University of Bristol, Bristol, UK. 43Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany. 44Department of Nutrition and Dietetics, Harokopio University, Athens, Greece. 45Department of Neurosciences, University of Padova, Padua, Italy. 46College of Nursing, Seattle University, Seattle, WA, USA. 47Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA. 48Department of Psychiatry, Athens University Medical School, Athens University, Athens, Greece. 49L’institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France. 50L’institut du thorax, CHU Nantes, Nantes, France. 51Department of Psychiatric Genetics, Poznań University of Medical Sciences, Poznań, Poland. 52Barcelona Institute of Science and Technology, Barcelona, Spain. 53Universitat Pompeu Fabra, Barcelona, Spain. 54Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. 55Department of Psychiatry and Behavioral Sciences, Stanford University Stanford, CA, USA. 56Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Centre for Mental Health, Würzburg, Germany. 57Estonian Genome Center, University of Tartu, Tartu, Estonia. 58Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. 59Genomics and Disease, Bioinformatics and Genomics Programme, Centre for Genomic Regulation, Barcelona, Spain. 60Department of Psychiatry, University Hospital of Bellvitge –IDIBELL and CIBERobn, Barcelona, Spain. 61Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain. 62Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Munich, Germany. 63Schön Klinik Roseneck affiliated with the Medical Faculty of the University of Munich (LMU), Munich, Germany. 64Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 65Department of Cancer, Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. 66Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany. 67Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. 68Department of Psychiatry (UPK), University of Basel, Basel, Switzerland. 69Department of Biomedicine, University of Basel, Basel, Switzerland. 70Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. 71Department of Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany. 721st Psychiatric Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece. 73QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 74CMME (Groupe Hospitalier Sainte-Anne), Paris Descartes University, Paris, France. 75Department of Biomedicine, Aarhus University, Aarhus, Denmark. 76The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSyCH), Aarhus, Denmark. 77Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark. 78Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. 79Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 80Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 81Department of Psychiatry, Weill Cornell Medical College, New york, Ny, USA. 82Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, London, UK. 83Department of Adult Psychiatry, Poznań University of Medical Sciences, Poznań, Poland. 84Zorg op Orde, Leidschendam, the Netherlands. 85Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. 86Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany. 87Department of Psychiatry, and Genetics and Genomics Sciences, Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New york, Ny, USA. 88Biological Psychiatry Laboratory, McLean Hospital/Harvard Medical School, Boston, MA, USA. 89Eating Disorders Unit, Parklandklinik, Bad Wildungen, Germany. 90Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, Isehara, Japan. 91Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic. 92Eating Recovery Center, Denver, CO, USA. 93Department of Psychological Medicine, University of Otago, Christchurch, New Zealand. 94Canterbury District Health Board, Christchurch, New Zealand. 95Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain. 96Department of Psychiatry, First Faculty of Medicine, Charles University, Prague, Czech Republic. 97Center for Addiction and Mental Health, Department of Psychiatry, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 98Department of Public Health, University of Helsinki, Helsinki, Finland. 99Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland. 100Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. 101Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria. 102Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands. 103Department of Psychiatry, University of California San Diego, San Diego, CA, USA. 104Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand. 105Health Services Research Unit, University of Aberdeen, Aberdeen, UK. 106Department of Psychiatry, Seoul Paik Hospital, Inje University, Seoul, Korea. 107Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. 108Department of Psychology, Michigan State University, East Lansing, MI, USA. 109Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway. 110National Centre for Register-Based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark. 111Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark. 112Department of Clinical Science, K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), University of Bergen, Bergen, Norway. 113Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. 114Department of Clinical Medicine, Laboratory Building, Haukeland University Hospital, Bergen, Norway. 115Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 116American School of Professional Psychology, Argosy University, Northern Virginia, Arlington, VA, USA. 117Department of Cancer Epidemiology and Prevention, M Skłodowska-Curie Cancer Center - Oncology Center, Warsaw, Poland. 118BESE Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia. 119Department of Psychiatry, University of Lausanne-University Hospital of Lausanne (UNIL-CHUV), Lausanne, Switzerland. 120Department of Psychiatry, University of Campania ‘Luigi Vanvitelli’, Naples, Italy. 121Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. 122Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 123Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany. 124Department of Psychiatry, University College Cork, Cork, Ireland. 125Eist Linn Adolescent Unit, Bessborough, Health Service Executive South, Cork, Ireland. 126Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. 127Molecular Epidemiology Section (Department of Medical Statistics), Leiden University Medical Centre, Leiden, the Netherlands. 128Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 129Division of Child and Adolescent Psychiatry, Geneva University Hospital, Geneva, Switzerland. 130Department of Psychiatry and Behavioral Science, University of North Dakota School of Medicine and Health Sciences, Fargo, ND, USA. 131National Center for PTSD, VA Boston Healthcare System, Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA. 132Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, Salerno, Italy. 133Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. 134Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy. 135Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. 136Kartini Clinic, Portland, OR, USA. 137Center for Human Genome Research at the Massachusetts General Hospital, Boston, MA, USA. 138Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand. 139Saint Joan de Déu Research Institute, Saint Joan de Déu Barcelona Children’s Hospital, Barcelona, Spain. 140Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain. 141Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain. 142Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 143Department of Health Science, University of Florence, Florence, Italy. 144Department of Biometry, University of Helsinki, Helsinki, Finland. 145Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 146Stanley Center for Psychiatric Research, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. 147Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany. 148Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. 149Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnologies, University of Pisa, Pisa, Italy. 150Department of Psychiatry, Poznań University of Medical Sciences, Poznań, Poland. 151Department of Neurosciences, Padua Neuroscience Center, University of Padova, Padua, Italy. 152Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Germany. 153Department of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. 154J. Craig Venter Institute (JCVI), La Jolla, CA, USA. 155Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria. 156Department of Pediatrics and Center of Applied Genomics, First Faculty of Medicine, Charles University, Prague, Czech Republic. 157Center for Eating Disorders Ursula, Rivierduinen, Leiden, the Netherlands. 158Department of Psychiatry, Leiden University Medical Centre, Leiden, the Netherlands. 159Department of Child and Adolescent Psychiatry, Poznań University of Medical Sciences, Poznań, Poland. 160IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. 161Department of Psychiatry and Biobehavioral Science, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. 162David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 163Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 164Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland. 165Department of Psychiatry, University of Naples SUN, Naples, Italy. 166Department of Psychiatry, University of Perugia, Perugia, Italy. 167Brain Sciences Department, Stremble Ventures, Limassol, Cyprus. 168Adolescent Health Unit, Second Department of Pediatrics, ‘P. & A. Kyriakou’ Children’s Hospital, University of Athens, Athens, Greece. 169Pediatric Intensive Care Unit, ‘P. & A. Kyriakou’ Children’s Hospital, University of Athens, Athens, Greece. 170Faculty of Social and Behavioral Sciences, Utrecht University, Utrecht, the Netherlands. 171School of Psychology, Flinders University, Adelaide, South Australia, Australia. 172Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 173Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. 174Toronto General Hospital, Toronto, Ontario, Canada. 175Institute of Translational Genomics, Helmholtz Zentrum München, Neuherberg, Germany. 176Department of Internal Medicine VI, Psychosomatic Medicine and Psychotherapy, University Medical Hospital Tübingen, Tübingen, Germany International Headache Genetics Consortium Verneri Anttila177, Ville Artto178, Andrea Carmine Belin179, Irene de Boer180, Dorret I. Boomsma181, Sigrid Børte182, Daniel I. Chasman183, Lynn Cherkas184, Anne Francke Christensen185, Bru Cormand186, Ester Cuenca-Leon177, George Davey-Smith187, Martin Dichgans188, Cornelia van Duijn189, Tonu Esko57, Ann Louise Esserlind190, Michel Ferrari180, Rune R. Frants180, Tobias Freilinger191, Nick Furlotte192, Padhraig Gormley177, Lyn Griffiths193, Eija Hamalainen194, Thomas Folkmann Hansen6, Marjo Hiekkala195, M. Arfan Ikram189, Andres Ingason196, Marjo-Riitta Järvelin197, Risto Kajanne194, Mikko Kallela178, Jaakko Kaprio98,99, Mari Kaunisto195, Lisette J. A. Kogelman6, Christian Kubisch198, Mitja Kurki177, Tobias Kurth199, Lenore Launer200, Terho Lehtimaki201, Davor Lessel198, Lannie Ligthart181, Nadia Litterman192, Arn van den Maagdenberg180, Alfons Macaya202, Rainer Malik188, Massimo Mangino184, George McMahon187, Bertram Muller-Myhsok203, Benjamin M. Neale177, Carrie Northover192, Dale R. Nyholt193, Jes Olesen190, Aarno Palotie58,99,137, Priit Palta194, Linda Pedersen182, Nancy Pedersen1, Danielle Posthuma181, Patricia Pozo-Rosich204, Alice Pressman205, Olli Raitakari206, Markus Schürks199, Celia Sintas186, Kari Stefansson196, Hreinn Stefansson196, Stacy Steinberg196, David Strachan207, Gisela Terwindt180, Marta Vila-Pueyo202, Maija Wessman195, Bendik S. Winsvold182, Huiying Zhao193 and John Anker Zwart182 177Broad Institute of MIT and Harvard, Cambridge, MA, USA. 178Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. 179Karolinska Institutet, Stockholm, Sweden. 180Leiden University Medical Centre, Leiden, the Netherlands. 181VU University, Amsterdam, the Netherlands. 182Oslo University Hospital and University of Oslo, Oslo, Norway. 183Harvard Medical School, Cambridge, MA, USA. 184Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. 185Danish Headache Center, Copenhagen University Hospital, Copenhagen, Denmark. 186University of Barcelona, Barcelona, Spain. 187Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK. 188Institute for Stroke and Dementia Research, Munich, Germany. 189Erasmus University Medical Centre, Rotterdam, the Netherlands. 190Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup, Denmark. 191University of Tübingen, Tübingen, Germany. 19223&Me Inc., Mountain View, CA, USA. 193Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. 194Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 195Folkhälsan Institute of Genetics, Helsinki, Finland. 196Decode genetics Inc., Reykjavik, Iceland. 197University of Oulu, Biocenter Oulu, Finland. 198University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 199Harvard Medical School, Boston, MA, USA. 200National Institute on Aging, Bethesda, MD, USA. 201School of Medicine, University of Tampere, Tampere, Finland. 202Vall d’Hebron Research Institute, Barcelona, Spain. 203Max Planck Institute of Psychiatry, Munich, Germany. 204Headache Research Group, Universitat Autònoma de Barcelona, Barcelona, Spain. 205Sutter Health, Sacramento, CA, USA. 206Department of Medicine, University of Turku, Turku, Finland. 207Population Health Research Institute, St George’s University of London, London, UK. 23andMe Research Team Michelle Agee208, Babak Alipanahi208, Adam Auton208, Robert Bell208, Katarzyna Bryc208, Sarah Elson208, Pierre Fontanillas208, Nicholas Furlotte208, Karl Heilbron208, David Hinds208, Karen Huber208, Aaron Kleinman208, Nadia Litterman208, Jennifer McCreight208, Matthew McIntyre208, Joanna Mountain208, Elizabeth Noblin208, Carrie Northover208, Steven Pitts208, J. Sathirapongsasuti208, Olga Sazonova208, Janie Shelton208, Suyash Shringarpure208, Chao Tian208, Joyce Tung208, Vladimir Vacic208 and Catherine Wilson208 20823andMe, Inc., Mountain View, CA, US

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h2 = 12%) and MDD (h2 = 19%), and a significant cross-disorder genetic correlation (rG = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (PSNP ≤ 5 × 10−8) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (Pgene-based ≤ 0.05) with both migraine and MDD (Pbinomial-test = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher’s combined gene-based P values that surpassed the genome-wide significance threshold (PFisher’s-combined ≤ 3.6 × 10−6). Pathway analysis of genes with PFisher’s-combined ≤ 1 × 10−3 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD.

Objective: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. Methods: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13–16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. Results: Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67–1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97–1.13; relative change in T2 lesion volume: −0.11, 95% CI = −0.25 to 0.04; change in EDSS: −0.01, 95% CI = −0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56–1.07). Results were similar in categorical analyses using quintiles. Interpretation: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20–29.

In the version of this article initially published online, the affiliations for Bertram Muller-Myhsok and Patricia Pozo-Rosich were incorrect or incomplete. These errors have been corrected for the print, PDF and HTML versions of this article.

BACKGROUND: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. METHODS: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. FINDINGS: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (

© 2015 American Academy of Neurology. Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p 6.4 × 10-28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p 2.7 × 10-20 for the CE score in MO). Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

Genome-wide association studies (GWAS) are a novel and promising method to study genetic susceptibility factors for common disorders, including migraine.

To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b).In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer20 NU/mL was considered NAb-positive, with low (≥20-100 NU/mL), medium (≥100-400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years.NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers.Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-11) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-5), permuted threshold for genome-wide significance 7.7 x 10(-5)). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

BACKGROUND: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. METHODS: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. FINDINGS: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0.63, 95% CI 0.48-0.83; p=0.003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, 0.52-1.11; p=0.177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. INTERPRETATION: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. FUNDING: Bayer Schering Pharma. ispartof: The Lancet Neurology vol:8 issue:11 pages:987-997 ispartof: location:England status: published

Objective To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-β-1a) plus natalizumab 300mg (n = 589), or IFN-β-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. Ann Neurol 2007

Migraine is a common neurovascular brain disorder that is manifested in recurrent episodes of disabling headache. The aim of the present study was to compare the prevalence and heritability of migraine across six of the countries that participate in GenomEUtwin project including a total number of 29,717 twin pairs. Migraine was assessed by questionnaires that differed between most countries. It was most prevalent in Danish and Dutch females (32% and 34%, respectively), whereas the lowest prevalence was found in the younger and older Finnish cohorts (13% and 10%, respectively). The estimated genetic variance (heritability) was significant and the same between sexes in all countries. Heritability ranged from 34% to 57%, with lowest estimates in Australia, and highest estimates in the older cohort of Finland, the Netherlands, and Denmark. There was some indication that part of the genetic variance was non-additive, but this was significant in Sweden only. In addition to genetic factors, environmental effects that are non-shared between members of a twin pair contributed to the liability of migraine. After migraine definitions are homogenized among the participating countries, the GenomEUtwin project will provide a powerful resource to identify the genes involved in migraine.