Meta-Analysis

. 2022 Feb;54(2):152-160.

doi: 10.1038/s41588-021-00990-0. Epub 2022 Feb 3.

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

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, Affiliations

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. matti.pirinen@helsinki.fi.
⁵⁹ Department of Public Health, University of Helsinki, Helsinki, Finland. matti.pirinen@helsinki.fi.
⁶⁰ Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. matti.pirinen@helsinki.fi.

PMID: 35115687
PMCID: PMC8837554
DOI: 10.1038/s41588-021-00990-0

Meta-Analysis

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

Heidi Hautakangas et al. Nat Genet. 2022 Feb.

. 2022 Feb;54(2):152-160.

doi: 10.1038/s41588-021-00990-0. Epub 2022 Feb 3.

Authors

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. matti.pirinen@helsinki.fi.
⁵⁹ Department of Public Health, University of Helsinki, Helsinki, Finland. matti.pirinen@helsinki.fi.
⁶⁰ Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. matti.pirinen@helsinki.fi.

PMID: 35115687
PMCID: PMC8837554
DOI: 10.1038/s41588-021-00990-0

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.

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Conflict of interest statement

G.B., T.E.T., S.H.M., H.S. and K.S. are employees of deCODE genetics/Amgen. P.G. is a current employee and stockholder of GlaxoSmithKline but work was conducted while employed by Massachusetts General Hospital, Boston, MA, USA. T.F. reports possible competing interest for Electrocore (participation in clinical studies), Novartis (speakers’ honoraria, participation in advisory boards, participation in clinical studies), Teva (speakers’ honoraria, participation in advisory boards), Lilly (speakers’ honoraria, participation in clinical studies), and Bayer (speakers’ honoraria). M. Kallela has served on Advisory Boards for MSD and Allergan; has received funding for travel and/or speaker honoraria from MSD, Allergan, Teva, Novartis and Genzyme; has received compensation for producing educational material from Teva and Allergan; has received research support from Helsinki University Central Hospital; and holds stock/stock options and/or has received Board of Directors compensation from Helsinki Headache Center. T.K. reports having received honoraria from Eli Lilly, Newsenselab and Total for providing methodological advice and from the BMJ for editorial services. A.P. is the Scientific Director of the public–private partnership project FinnGen that has 12 industry partners that provide funding for the FinnGen project. V.A. has served on advisory board for Allergan, Lundbeck, Teva and Lilly. G.M.T. reports consultancy support from Novartis, Allergan, Lilly and Teva, and independent support from Dutch Organization for Scientific Research, the Dutch Heart & Brain Foundations, IRRF and Dioraphte. Other authors report no competing interests.

Figures

**Fig. 1. Manhattan plot of migraine GWAS meta-analysis (n = 873,341; 102,084 cases and 771,257 controls).**
On the x axis, variants are plotted along the 22 autosomes and the X chromosome. The y axis shows the statistical strength of the association from the inverse–variance weighted fixed-effect meta-analysis as the negative log₁₀ of the uncorrected two-sided P value (P). The horizontal line is the genome-wide significance threshold (P = 5 × 10⁻⁸). The 123 risk loci passing the threshold are divided into 86 new loci (purple) and 37 previously known loci (green). Adjacent chromosomes are colored in different shades of blue. Plotted are variants with P < 0.001.

**Fig. 2. LocusZoom plots of two previously unknown migraine loci with genes that are targets of recent migraine-specific drugs.**
a, Locus containing *CALCA* and *CALCB* genes, encoding CGRP, which is the target of preventive and acute therapies via monoclonal antibodies and gepants. b, Locus containing the *HTR1F* gene, which encodes a serotonin 5-HT_1F receptor that is the target of acute therapies via ditans. The x axis shows the chromosomal location, and the y axis shows the uncorrected two-sided negative log₁₀ (P) from the inverse–variance weighted fixed-effects meta-analysis with 102,084 cases and 771,257 controls. The squared correlation to the lead variant is shown by colors based on the UK Biobank data for variants that have an effective sample size ±20% of the lead variant’s effective sample size. Horizontal line corresponds to P = 5 × 10⁻⁸. Blue graph shows the recombination rate.

**Fig. 3. Lead variants stratified by migraine subtype for risk loci with MAF >5%.**
a, Axes show the negative log₁₀ (P) of MO (x axis; n = 697,356, 15,055 MO cases and 682,301 controls) and MA (y axis; n = 718,476, 14,624 MA cases and 703,852 controls) analyses. Two-sided P values are derived from inverse–variance weighted fixed-effect meta-analyses and are uncorrected. Symbols that are colored and annotated indicate >95% posterior probability that a nonzero effect is present in both MO and MA (model BOTH), or that the effect is present only in MO or only in MA but not both (models MO and MA, respectively). Variants with a probability <95% for each of the three models are shown as gray. Dashed lines show the genome-wide significance threshold (P = 5 × 10⁻⁸). b, Axes show logarithm of odds ratios (OR) for MO (x axis; n = 697,356, 15,055 MO cases and 682,301 controls) and MA (y axis; n = 718,476, 14,624 MA cases and 703,852 controls) calculated for the migraine risk allele. The effects at variants that have been colored and annotated differ between the subtypes at significance level of 0.0004 = 0.05/123. The 95% CIs for the logarithm of odds ratios are shown for the annotated variants. Dashed lines show the coordinate axes and the diagonal.

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References

1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia38, 1–211 (2018). - PubMed
1. Vos T, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–1222. - PMC - PubMed
1. Steiner TJ, et al. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J. Headache Pain. 2020;21:137. - PMC - PubMed
1. Russell MB, Rasmussen BK, Thorvaldsen PER, Olesen JES. Prevalence and sex-ratio of the subtypes of migraine. Int. J. Epidemiol. 1995;24:612–618. - PubMed
1. Russell MB, Olesen J. Increased familial risk and evidence of genetic factor in migraine. BMJ. 1995;311:541–544. - PMC - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous