Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Heidi Hautakangas; Bendik S Winsvold; Sanni E Ruotsalainen; Gyda Bjornsdottir; Aster V E Harder; Lisette J A Kogelman; Laurent F Thomas; Raymond Noordam; Christian Benner; Padhraig Gormley; Ville Artto; Karina Banasik; Anna Bjornsdottir; Dorret I Boomsma; Ben M Brumpton; Kristoffer Sølvsten Burgdorf; Julie E Buring; Mona Ameri Chalmer; Irene de Boer; Martin Dichgans; Christian Erikstrup; Markus Färkkilä; Maiken Elvestad Garbrielsen; Mohsen Ghanbari; Knut Hagen; Paavo Häppölä; Jouke-Jan Hottenga; Maria G Hrafnsdottir; Kristian Hveem; Marianne Bakke Johnsen; Mika Kähönen; Espen S Kristoffersen; Tobias Kurth; Terho Lehtimäki; Lannie Lighart; Sigurdur H Magnusson; Rainer Malik; Ole Birger Pedersen; Nadine Pelzer; Brenda W J H Penninx; Caroline Ran; Paul M Ridker; Frits R Rosendaal; Gudrun R Sigurdardottir; Anne Heidi Skogholt; Olafur A Sveinsson; Thorgeir E Thorgeirsson; Henrik Ullum; Lisanne S Vijfhuizen; Elisabeth Widén; Ko Willems van Dijk; International Headache Genetics Consortium; HUNT All-in Headache; Danish Blood Donor Study Genomic Cohort; Arpo Aromaa; Andrea Carmine Belin; Tobias Freilinger; M Arfan Ikram; Marjo-Riitta Järvelin; Olli T Raitakari; Gisela M Terwindt; Mikko Kallela; Maija Wessman; Jes Olesen; Daniel I Chasman; Dale R Nyholt; Hreinn Stefánsson; Kari Stefansson; Arn M J M van den Maagdenberg; Thomas Folkmann Hansen; Samuli Ripatti; John-Anker Zwart; Aarno Palotie; Matti Pirinen

doi:10.1038/s41588-021-00990-0

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Nat Genet. 2022 Feb;54(2):152-160. doi: 10.1038/s41588-021-00990-0. Epub 2022 Feb 3.

Authors

Heidi Hautakangas¹, Bendik S Winsvold^{2

3

4}, Sanni E Ruotsalainen¹, Gyda Bjornsdottir⁵, Aster V E Harder^{6

7}, Lisette J A Kogelman⁸, Laurent F Thomas^{3

9

10

11}, Raymond Noordam¹², Christian Benner¹, Padhraig Gormley¹³, Ville Artto¹⁴, Karina Banasik¹⁵, Anna Bjornsdottir¹⁶, Dorret I Boomsma¹⁷, Ben M Brumpton³, Kristoffer Sølvsten Burgdorf¹⁸, Julie E Buring^{19

20}, Mona Ameri Chalmer⁸, Irene de Boer⁶, Martin Dichgans^{21

22}, Christian Erikstrup²³, Markus Färkkilä¹⁴, Maiken Elvestad Garbrielsen³, Mohsen Ghanbari²⁴, Knut Hagen^{25

26}, Paavo Häppölä¹, Jouke-Jan Hottenga¹⁷, Maria G Hrafnsdottir²⁷, Kristian Hveem^{3

28}, Marianne Bakke Johnsen^{3

29

30}, Mika Kähönen³¹, Espen S Kristoffersen^{30

32

33}, Tobias Kurth³⁴, Terho Lehtimäki³⁵, Lannie Lighart¹⁷, Sigurdur H Magnusson⁵, Rainer Malik²¹, Ole Birger Pedersen³⁶, Nadine Pelzer⁶, Brenda W J H Penninx^{37

38}, Caroline Ran³⁹, Paul M Ridker^{19

20}, Frits R Rosendaal⁴⁰, Gudrun R Sigurdardottir¹⁶, Anne Heidi Skogholt³, Olafur A Sveinsson²⁷, Thorgeir E Thorgeirsson⁵, Henrik Ullum¹⁸, Lisanne S Vijfhuizen⁷, Elisabeth Widén¹, Ko Willems van Dijk^{7

41}; International Headache Genetics Consortium; HUNT All-in Headache; Danish Blood Donor Study Genomic Cohort; Arpo Aromaa⁴², Andrea Carmine Belin³⁹, Tobias Freilinger^{43

44}, M Arfan Ikram²⁴, Marjo-Riitta Järvelin^{45

46

47

48}, Olli T Raitakari^{49

50

51}, Gisela M Terwindt⁶, Mikko Kallela¹⁴, Maija Wessman^{1

52}, Jes Olesen⁸, Daniel I Chasman^{19

20}, Dale R Nyholt⁵³, Hreinn Stefánsson⁵, Kari Stefansson⁵, Arn M J M van den Maagdenberg^{6

7}, Thomas Folkmann Hansen^{8

15}, Samuli Ripatti^{1

54

55}, John-Anker Zwart^{2

3

29}, Aarno Palotie^{1

56

57}, Matti Pirinen^{58

59

60}

Collaborators

Irene de Boer, Arn M J M van den Maagdenberg

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
² Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
³ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁵ deCODE genetics/Amgen Inc., Reykjavik, Iceland.
⁶ Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁸ Danish Headache Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark.
⁹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹² Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
¹³ GlaxoSmithKline, Cambridge, MA, USA.
¹⁴ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
¹⁵ Novo Nordic Foundation Center for Protein Research, Copenhagen University, Copenhagen, Denmark.
¹⁶ Neurology Private Practice, Laeknasetrid, Reykjavik, Iceland.
¹⁷ Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
¹⁸ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁰ Harvard Medical School, Boston, MA, USA.
²¹ Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.
²² Munich Cluster for Systems Neurology (Synergy), Munich, Germany.
²³ Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
²⁴ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
²⁵ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²⁶ Clinical Research Unit Central Norway, St. Olavs University Hospital, Trondheim, Norway.
²⁷ Landspitali University Hospital, Reykjavik, Iceland.
²⁸ HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
²⁹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
³⁰ Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
³¹ Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
³² Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway.
³³ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
³⁴ Institute of Public Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³⁵ Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
³⁶ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
³⁷ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
³⁸ GGZ inGeest Specialized Mental Health Care, Amsterdam, the Netherlands.
³⁹ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁴⁰ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁴¹ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
⁴² National Public Health Institute (Finnish Institute for Health and Welfare - THL), Helsinki, Finland.
⁴³ Klinikum Passau, Department of Neurology, Passau, Germany.
⁴⁴ Centre of Neurology, Hertie Institute for Clinical Brain Research, Tuebingen, Germany.
⁴⁵ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁴⁶ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁴⁷ Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland.
⁴⁸ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
⁴⁹ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁵⁰ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁵¹ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁵² Folkhälsan Research Center, Helsinki, Finland.
⁵³ School of Biomedical Sciences and Centre for Genomics and Personalised Health, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
⁵⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵⁵ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁵⁶ Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁵⁷ The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵⁸ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland. [email protected].
⁵⁹ Department of Public Health, University of Helsinki, Helsinki, Finland. [email protected].
⁶⁰ Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. [email protected].

Abstract

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Cardiovascular System / metabolism
Case-Control Studies
Central Nervous System / metabolism
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Migraine Disorders / genetics*
Migraine with Aura / genetics
Molecular Sequence Annotation
Polymorphism, Single Nucleotide*
Quantitative Trait Loci

Abstract

Publication types

MeSH terms

Grants and funding