Introduction

Migraine is a debilitating and highly prevalent chronic pain condition that is a leading contributor to disability worldwide.¹ By the time of clinical presentation, those with migraine are more likely to report several comorbidities, including several sleep disturbances and disorders (reviewed by Vgontzas and Pavlović).^2-6 Prospective studies have found associations between insomnia and increased risk for incident migraine diagnosis⁷ and vice versa. Despite this epidemiologic evidence, there remain several unanswered questions about the relationship between migraine and sleep. Although both migraine (SNP-based heritability 15%)⁸ and sleep traits (SNP-based heritability ranging from 6.9% to 17%)^9-12 are heritable, it is unknown whether this comorbidity is driven, at least partly, by shared genetic influences. It is also unknown whether causality underlies this comorbidity,⁴ as associations in epidemiologic studies are potentially biased by residual confounding and reverse causality. Delineating causality between sleep patterns and migraine may offer new pathophysiologic insights into these traits and inform subsequent intervention trials.

Causality can be investigated using Mendelian randomization (MR).¹³ MR can be conceptualized as a natural experiment whereby individuals are randomly allocated to lifelong greater exposure to a given risk factor (e.g., insomnia symptoms) based on their genetic risk, and then the risk of a disease outcome (e.g., migraine) as a function of this exposure is measured later in life.¹⁴ The validity of this approach rests on the random assortment of genetic alleles at gametogenesis, thereby rendering the alleles relatively unconfounded by environmental factors. Moreover, inherited genetic variation is fixed at birth and is therefore not modifiable by environmental factors or disease status. MR has been previously used to examine causal relationships between migraine and dementia,¹⁵ blood pressure,¹⁶ and cardiovascular disease.^{17, 18}

The availability of large-scale genome-wide association studies (GWAS) for sleep traits^9-12 (n ≤ 452,071) and migraine⁸ (n = 375,752) now provides an opportunity to test shared genetic predisposition and causal effects. Here, we leveraged cross-trait LD Score regression¹⁹ and MR²⁰ using recently available data from the UK Biobank cohort and the largest GWAS of migraine⁸ to, respectively, assess for a shared genetic basis and for potential causal effects between sleep traits and migraine.

Methods

Mendelian randomization analyses

The design of our MR analysis is shown in Figure 1, with details of data harmonization provided in the Data S1. The primary MR method was random-effects inverse-variance weighted (IVW) regression,²⁶ with sleep and migraine alternately used as exposure or outcome. For ordinal phenotypes (Table S1), a one-unit increase in the genetic instrument corresponds to a unit increase in the ordinal scale. For dichotomous phenotypes, a one-unit increase in the genetic instrument reflects a doubling in the odds of the exposure trait.²⁷

Results

Mendelian randomization analyses support causal effects of difficulty awakening and insomnia symptoms on migraine

To investigate whether any of the sleep traits causally influence migraine susceptibility, we performed two-sample MR analyses using established genetic signals to proxy each of the sleep exposures (Fig. 2; Table S1). There was evidence for a significant effect of difficulty awakening on migraine (OR [95% CI] 1.37 [1.12–1.68], P = 0.002). There was also nominal evidence for an effect of liability to insomnia symptoms on migraine (1.09 [1.02–1.16], P = 0.015). Removing weakly correlated SNPs (using a stricter clumping threshold of r² < 0.001 vs. r² < 0.01) yielded nearly identical effect estimates for insomnia (36 SNPs; 1.09 [1.01–1.17], P = 0.019) and for difficulty awakening (71 SNPs; 1.37 [1.10–1.71], P = 0.006). MR estimates were null for the effect of all other sleep traits on migraine susceptibility (Fig. 2).

Mendelian randomization does not support causal effects of migraine on sleep patterns and disturbances

We next assessed whether genetic liability to migraine impacted habitual sleep patterns and disturbances. Genetically predicted liability to migraine did not significantly influence any sleep disturbances, with confidence intervals excluding large effects (Fig. 3; Table S8). There was suggestive evidence for a weak effect of migraine liability on increased napping (0.01 unit increase in napping frequency [0.003, 0.017], P = 0.007), with consistent estimates across sensitivity analyses (Table S9).

Discussion

We leveraged genetic methods to investigate comorbidity and causality between migraine and sleep disturbances. We found evidence for shared genetic influences between multiple sleep traits and migraine, as well as potential causal effects of insomnia symptoms and difficulty awakening on migraine. These effects were robust in sensitivity analyses for horizontal pleiotropy and there was no evidence for strong effects in the reverse direction.

We found evidence f shared genetic influences between several sleep traits and migraine, with the strongest genetic correlation found with insomnia symptoms (rg = 0.29). With the exception of a previously reported genetic correlation of migraine with MDD of 0.32, the magnitude of genetic overlap between insomnia and migraine was greater than that reported for most other common disease traits in the UK Biobank¹⁸ and in previous studies,^{16, 31, 32} suggesting more shared underlying biology between migraine and insomnia than migraine and other cardiometabolic, neuropsychiatric and immune phenotypes. Weaker but highly significant correlations of migraine were seen with other sleep duration and quality traits, confirming that the highly pleiotropic migraine genetic loci also influence sleep traits. As the sample size for migraine GWAS grows, future cross-phenotype analyses may identify specific loci underlying these genetic correlations. Although prior work has demonstrated that rare mutations in the casein kinase (CK Iδ) gene may simultaneously cause familial migraine and advanced sleep phase syndrome,³³ our work showed no evidence for an overall shared genetic basis for migraine and morning diurnal preference. This suggests that genetic variation in circadian rhythms may not generally have an important effect on migraine etiology, but certain circadian genes (e.g., CK Iδ) may have pleiotropic roles in migraine via pathways unrelated to their circadian effects.³³

Mendelian randomization analyses suggested a causal effect of insomnia symptoms on migraine, adding support to findings from prospective epidemiologic studies.⁷ This estimate was consistent across sensitivity analyses, and was stronger in a secondary analysis using a larger number of insomnia SNPs from a meta-analysis of UK Biobank and 23andMe. These variants were only used in sensitivity analyses because sample overlap of the insomnia symptoms GWAS (288,557 insomnia cases and 655,920 controls from 23andMe)²⁴ with the migraine GWAS (30,465 migraine cases and 143,147 controls from 23andMe)⁸ may bias effect estimates away from the null. However, this bias is unlikely to be large given that the degree of case overlap is not large (up to 30,465 migraine GWAS cases included in the insomnia GWAS of n = 1,331,010; 3%) and that the genetic instrument for insomnia is strong (F-statistic > 10).³⁴ Given the nominal statistical evidence for this finding, additional replication in independent samples with well-defined and validated diagnostic criteria for insomnia will strengthen confidence in this effect. Nevertheless, the evidence from this study supports findings from longitudinal epidemiologic studies of insomnia and migraine (reviewed by Uhlig et al.).⁷ One of the largest studies to date (26,197 participants from the HUNT study) reported that individuals with insomnia at baseline had a relative risk of 1.40 (95% CI 1.0–1.9; P = 0.02) for migraine after 11 years of follow up.³⁵ Our results are also consistent with evidence from a clinical trial of cognitive behavioral therapy for insomnia in patients with migraine, in which treatment of insomnia reduced migraine frequency.³⁶ Although insomnia symptoms are genetically correlated with short sleep duration,^{9, 12} there was no significant effect of genetically proxied self-reported short sleep duration on migraine. This is in contrast to prior MR analyses which found concordant effects of insomnia and short sleep duration on coronary artery disease risk,^{9, 37} suggesting that the short sleep component of insomnia may be less relevant to the etiology of migraine. Rather, other features of insomnia such as hyperarousal may play more prominent roles in the etiology of migraine.³⁸

Relative to insomnia, less is known about the phenomenon of difficulty awakening, which in some settings is referred to as sleep inertia.^{39, 40} Difficulty awakening is inversely genetically correlated²⁴ with morning diurnal preference (rg = −0.78) and with insomnia symptoms (rg = 0.23) and may therefore reflect a combination of circadian misalignment and interrupted sleep.^{24, 39} However, we did not find evidence for a causal effect of morning diurnal preference on migraine. This suggests that the effect of difficulty awakening on migraine may be driven by disturbances to sleep quality rather than through circadian mechanisms. Difficulty awakening⁴⁰ may also be a consequence of psychiatric comorbidities, and prior work has highlighted genetic correlations between sleep and psychiatric comorbidities,^{9, 12} and between migraine and psychiatric disease.³¹ This motivated multivariable MR analyses adjusting MR estimates for potential pleiotropy with MDD and with anxious symptoms. We found partial attenuation of the MR estimates for both difficulty awakening and insomnia symptoms on migraine when adjusting for MDD, however the adjusted MR estimate remained significant. This finding is consistent with prior epidemiologic analyses that have shown that sleep disturbances influence migraine risk independently of MDD and anxiety.⁴¹ This suggests that sleep disturbances directly influence migraine risk independently of psychiatric comorbidities and therefore warrant intervention in their own right.

There was minimal evidence for an effect of migraine on any of the sleep patterns or disturbances. While longitudinal epidemiologic studies lasting up to 11 years have suggested potential effects of migraine on insomnia risk,^{7, 35} our results are in line with microlongitudinal studies that have not shown effects of migraine headaches on next-day sleep.⁴² We did, however, identify a small effect of migraine liability on increased napping frequency. The use of naps as an acute abortive treatment for migraine² may be one possible mechanism mediating this effect. The generally null effects of migraine on habitual sleep patterns do not exclude an acute effect of a migraine episode on sleep. An analogy may be drawn to the relationship of caffeine with sleep, where MR analyses have not shown causal effects of caffeine on sleep patterns,⁴³ suggesting discordance between effects of short and long-term caffeine consumption. Similarly, while a migraine headache may acutely interrupt sleep, we did not find strong evidence for effects of migraine liability on sustained sleep patterns.

There are several potential pathways by which sleep quality or insomnia symptoms may influence migraine susceptibility. Cortical excitability, a potential mechanism of migraine pathophysiology,⁴⁴ may be increased by insomnia.⁴⁵ Sleep disturbances^{2, 46} may also reduce pain thresholds⁴⁷ and cause dysfunction of the glymphatic system, resulting in accumulation of nociceptive CNS waste.^{4, 41} Finally, difficulty awakening may reflect slow clearance of CNS adenosine,³⁹ with the consequent increases in adenosine increasing the likelihood of headache onset.⁴⁸ Additional work is necessary to determine which of these pathways, if any, are relevant to the effect of sleep disturbances on migraine.

We acknowledge limitations to this work. First, although we incorporated sensitivity analyses for horizontal pleiotropy, we cannot fully exclude the influence of this potential bias. Second, MR power calculators are not currently designed for ordinal or binary exposures, so we focused on interpretation of the confidence intervals to determine whether the bounds contained clinically relevant effects. Third, single, self-reported questions are less reliable for phenotyping than validated scales or physician-diagnosed insomnia, which were unavailable in UKB. Fourth, the known common variant contributions to migraine primarily reflect the genetic architecture of migraine without aura (MO), which is the most prevalent form of migraine.⁸ Our findings may therefore have greater relevance to the pain component of migraine, which is more prominent in MO.⁴⁹ This limitation may be addressed in future analyses as genetic data on migraine with aura become more robust. Finally, the selection of relatively healthy individuals into UKB may limit generalizability to less healthy populations and to populations of non-European ancestry.

Conclusion

The genetic determinants of sleep and migraine are partly overlapping. Sleep disturbances may causally influence migraine etiology, and are promising targets for the treatment of migraine.

Author Contributions

ID and RS conceived and designed the study with input from all coauthors. RS and DC provided the data. ID and YG analyzed the data. ID drafted the initial manuscript. RS, AV, YG, and DC provided critical feedback to the manuscript and approved the final version. ID and RS are the guarantors. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

International Headache Genetics Consortium Members

Padhraig Gormley³¹⁻³⁴, Verneri Anttila^32,33,35, Bendik S. Winsvold³⁶⁻³⁸, Priit Palta³⁹, Tonu Esko^32,40,41, Tune H. Pers^32,41−43, Kai-How Farh^32,35,44, Ester Cuenca-Leon^31−33,45, Mikko Muona^39,46−48, Nicholas A. Furlotte³⁰, Tobias Kurth^49,9, Andres Ingason¹⁰, George McMahon⁵⁰, Lannie Ligthart⁵¹, Gisela M. Terwindt⁵², Mikko Kallela⁵³, Tobias M. Freilinger^54,55, Caroline Ran⁵⁶, Scott G. Gordon²², Anine H. Stam⁵², Stacy Steinberg¹⁰, Guntram Borck⁵⁷, Markku Koiranen⁵⁸, Lydia Quaye⁵⁹, Hieab H. H. Adams^6,61, Terho Lehtimäki⁶², Antti-Pekka Sarin³⁹, Juho Wedenoja⁶³, David A. Hinds³⁰, Julie E. Buring^9,64, Markus Schürks⁶⁵, Paul M. Ridker^9,64, Maria Gudlaug Hrafnsdottir⁶⁶, Hreinn Stefansson¹⁰, Susan M. Ring⁵⁰, Jouke-Jan Hottenga⁵¹, Brenda W. J. H. Penninx⁶⁷, Markus Färkkilä⁵³, Ville Artto⁵³, Mari Kaunisto³⁹, Salli Vepsäläinen⁵³, Rainer Malik⁵⁵, Andrew C. Heath⁶⁸, Pamela A. F. Madden⁶⁸, Nicholas G. Martin²², Grant W. Montgomery⁸, Mitja I. Kurki^{31−33,39,69}, Mart Kals⁴⁰, Reedik Mägi⁴⁰, Kalle Pärn⁴⁰, Eija Hämäläinen³⁹, Hailiang Huang^32,33,35, Andrea E. Byrnes^32,33,35, Lude Franke⁷⁰, Jie Huang³⁴, Evie Stergiakouli⁵⁰, Phil H. Lee³¹⁻³³, Cynthia Sandor⁷¹, Caleb Webber⁷¹, Zameel Cader^72,73, Bertram Muller-Myhsok^74,75, Stefan Schreiber⁷⁶, Thomas Meitinger^77,78, Johan G. Eriksson^79,8, Veikko Salomaa⁸⁰, Kauko Heikkilä⁸¹, Elizabeth Loehrer^60,82, Andre G. Uitterlinden⁸³, Albert Hofman⁶⁰, Cornelia M. van Duijn⁶⁰, Lynn Cherkas⁵⁹, Linda M. Pedersen³⁶, Audun Stubhaug^84,85, Christopher S. Nielsen^84,86, Minna Männikkö⁵⁸, Evelin Mihailov⁴⁰, Lili Milani⁴⁰, Hartmut Göbel⁸⁷, Ann-Louise Esserlind⁸⁸, Anne Francke Christensen⁸⁸, Thomas Folkmann Hansen⁸⁹, Thomas Werge^90,91,7, Jaakko Kaprio^39,63,92, Arpo J. Aromaa⁸⁰, Olli Raitakari^93,94, M. Arfan Ikram^60,61,95, Tim Spector⁵⁹, Marjo-Riitta Järvelin^58,96−98, Andres Metspalu⁴⁰, Christian Kubisch⁹⁹, David P. Strachan¹⁰⁰, Michel D. Ferrari⁵², Andrea C. Belin⁵⁶, Martin Dichgans^55,75, Maija Wessman^39,46, Arn M. J. M. van den Maagdenberg^52,101, John-Anker Zwart³⁶⁻³⁸, Dorret I. Boomsma⁵¹, George Davey Smith⁵⁰, Kari Stefansson^10,102, Nicholas Eriksson³⁰, Mark J. Daly^32,33,35, Benjamin M. Neale^32,33,35, Jes Olesen⁸⁸, Daniel I. Chasman⁹, Dale R. Nyholt¹, Aarno Palotie^31−35,103.

International Headache Genetics Consortium Affiliations

¹School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. ²Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA. ³23andMe, Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA. ⁴School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom. ⁵Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 950-2181, Japan. ⁶Department of Biomedicine - Human Genetics, Aarhus University, DK-8000 Aarhus, Denmark. ⁷iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark. ⁸Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. ⁹Divisions of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. ¹⁰deCODE Genetics/Amgen, 101 Reykjavik, Iceland. ¹¹Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK. ¹²Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.¹³KULeuven, Department of Development and Regeneration, Organ systems, 3000 Leuven, Belgium. ¹⁴Department of Obstetrics and Gynaecology, Leuven University Fertility Centre, University Hospital Leuven, 3000 Leuven, Belgium. ¹⁵Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA. ¹⁶Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ¹⁷Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA. ¹⁸Institute of Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. ¹⁹Vanderbilt Genetics Institute, Division of Epidemiology, Institute of Medicine and Public Health, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. ²⁰Cognitive Science Department, University of California, San Diego, La Jolla, California 92093, USA. ²¹Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. ²²Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. ²³Endometriosis CaRe Centre, Nuffield Dept of Obstetrics & Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. ²⁴Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ²⁵Institute of Medical Sciences, The University of Tokyo, Tokyo 108-8639, Japan. ²⁶Department of Obstetrics and Gynecology, Landspitali University Hospital, 101 Reykjavik, Iceland. ²⁷Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. ²⁸Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute of Medicine and Public Health, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. ²⁹Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. ³⁰23andMe, Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA. ³¹Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. ³²Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. ³³Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. ³⁴Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. ³⁵Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. ³⁶FORMI, Oslo University Hospital, Oslo, Norway. ³⁷Department of Neurology, Oslo University Hospital, Oslo, Norway. ³⁸Institute of Clinical Medicine, University of Oslo, Oslo, Norway. ³⁹Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. ⁴⁰Estonian Genome Center, University of Tartu, Tartu, Estonia. ⁴¹Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA. ⁴²Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. ⁴³Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. ⁴⁴Illumina, San Diego, California, USA. ⁴⁵Pediatric Neurology, Vall d’Hebron Research Institute, Barcelona, Spain. ⁴⁶Folkhälsan Institute of Genetics, Helsinki, Finland. ⁴⁷Neuroscience Center, University of Helsinki, Helsinki, Finland. ⁴⁸Molecular Neurology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. ⁴⁹Institute of Public Health, Charité–Universitätsmedizin Berlin, Berlin, Germany. ⁵⁰Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK. ⁵¹Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands. ⁵²Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands. ⁵³Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. ⁵⁴Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. ⁵⁵Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. ⁵⁶Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. ⁵⁷Institute of Human Genetics, Ulm University, Ulm, Germany. ⁵⁸Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland. ⁵⁹Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. ⁶⁰Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. ⁶¹Department of Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands. ⁶²Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland. ⁶³Department of Public Health, University of Helsinki, Helsinki, Finland. ⁶⁴Harvard Medical School, Boston, Massachusetts, USA. ⁶⁵Department of Neurology, University Duisburg–Essen, Essen, Germany. ⁶⁶Landspitali University Hospital, Reykjavik, Iceland. ⁶⁷Department of Psychiatry, VU University Medical Centre, Amsterdam, the Netherlands. ⁶⁸Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. ⁶⁹Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland. ⁷⁰Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. ⁷¹MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, UK. ⁷²Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK. ⁷³Oxford Headache Centre, John Radcliffe Hospital, Oxford, UK. ⁷⁴Max Planck Institute of Psychiatry, Munich, Germany. ⁷⁵Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. ⁷⁶Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany. ⁷⁷Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. ⁷⁸Institute of Human Genetics, Technische Universität München, Munich, Germany. ⁷⁹Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. ⁸⁰National Institute for Health and Welfare, Helsinki, Finland. ⁸¹Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland. ⁸²Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. ⁸³Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands. ⁸⁴Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway. ⁸⁵Medical Faculty, University of Oslo, Oslo, Norway. ⁸⁶Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway. ⁸⁷Kiel Pain and Headache Center, Kiel, Germany. ⁸⁸Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark. ⁸⁹Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark. ⁹⁰Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark. ⁹¹Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark. ⁹²Department of Health, National Institute for Health and Welfare, Helsinki, Finland. ⁹³Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. ⁹⁴Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. ⁹⁵Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands. ⁹⁶Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK. ⁹⁷Biocenter Oulu, University of Oulu, Oulu, Finland. ⁹⁸Unit of Primary Care, Oulu University Hospital, Oulu, Finland. ⁹⁹Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ¹⁰⁰Population Health Research Institute, St George’s, University of London, London, UK. ¹⁰¹Department of Human Genetics, Leiden University Medical Centre, Leiden, the Net herlands. ¹⁰²Faculty of Medicine, University of Iceland, Reykjavik, Iceland. ¹⁰³Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Conflicts of Interest

The authors declare no conflicts of interest.