Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Nature Genetics volume 43, pages 695–698 (2011)Cite this article

Subjects

Abstract

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10−6) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10−9; rs10166942, OR = 0.85, P = 5.5 × 10−12; and rs11172113, OR = 0.90, P = 4.3 × 10−9). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Association P values and genomic context for candidate SNPs.

Similar content being viewed by others

References

  1. Haut, S.R., Bigal, M.E. & Lipton, R.B. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol. 5, 148–157 (2006).

    Article  Google Scholar 

  2. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24 (Suppl 1), 9–160 (2004).

  3. Mulder, E.J. et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res. 6, 422–431 (2003).

    Article  Google Scholar 

  4. de Vries, B., Frants, R.R., Ferrari, M.D. & van den Maagdenberg, A.M. Molecular genetics of migraine. Hum. Genet. 126, 115–132 (2009).

    Article  Google Scholar 

  5. Anttila, V. et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat. Genet. 42, 869–873 (2010).

    Article  CAS  Google Scholar 

  6. Ridker, P.M. et al. Rationale, design, and methodology of the Women's Genome Health Study: a genome-wide association study of more than 25,000 initially healthy American women. Clin. Chem. 54, 249–255 (2008).

    Article  CAS  Google Scholar 

  7. Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    Article  CAS  Google Scholar 

  8. Launer, L.J., Terwindt, G.M. & Ferrari, M.D. The prevalence and characteristics of migraine in a population-based cohort: the GEM study. Neurology 53, 537–542 (1999).

    Article  CAS  Google Scholar 

  9. Völzke, H. et al. Cohort profile: the study of health in pomerania. Int. J. Epidemiol. 40, 294–307 (2011).

    Article  Google Scholar 

  10. Proudfoot, C.J. et al. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr. Biol. 16, 1591–1605 (2006).

    Article  CAS  Google Scholar 

  11. Peier, A.M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002).

    Article  CAS  Google Scholar 

  12. Dray, A. Neuropathic pain: emerging treatments. Br. J. Anaesth. 101, 48–58 (2008).

    Article  CAS  Google Scholar 

  13. Biondi, D.M. Is migraine a neuropathic pain syndrome? Curr. Pain Headache Rep. 10, 167–178 (2006).

    Article  Google Scholar 

  14. Lillis, A.P., Van Duyn, L.B., Murphy-Ullrich, J.E. & Strickland, D.K. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 88, 887–918 (2008).

    Article  CAS  Google Scholar 

  15. Andreou, A.P. & Goadsby, P.J. Therapeutic potential of novel glutamate receptor antagonists in migraine. Expert Opin. Investig. Drugs 18, 789–803 (2009).

    Article  CAS  Google Scholar 

  16. Secker-Walker, L.M., Mehta, A. & Bain, B. Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study. Br. J. Haematol. 91, 490–501 (1995).

    Article  CAS  Google Scholar 

  17. Seale, P., Kajimura, S. & Spiegelman, B.M. Transcriptional control of brown adipocyte development and physiological function–of mice and men. Genes Dev. 23, 788–797 (2009).

    Article  CAS  Google Scholar 

  18. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  19. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Article  CAS  Google Scholar 

  20. Marchini, J. & Howie, B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 11, 499–511 (2010).

    Article  CAS  Google Scholar 

  21. Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

    Article  Google Scholar 

  22. Hirschhorn, J.N. & Daly, M.J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005).

    Article  CAS  Google Scholar 

  23. Mägi, R. & Morris, A.P. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).

    Article  Google Scholar 

  24. Viechtbauer, W. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36, 1–48 (2010).

    Article  Google Scholar 

  25. Hindorff, L.A., Junkins, H.A., Hall, P.N., Mehta, J.P. & Manolio, T.A. A catalog of published genome-wide association studies. &lt;http://www.genome.gov/gwastudies/&gt;. (accessed 18 August 2010).

  26. Johnson, A.D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study is supported by a grant from the National Institute of Neurological Disorders and Stroke (NS-061836). The Women's Health Study and the Women's Genome Health Study are supported by grants from the National Heart, Lung, and Blood Institute (HL-043851, HL-080467 and HL-099355) and the National Cancer Institute (CA-47988). Part of the research for this work was supported by grants from the Donald W. Reynolds Foundation and the Leducq Foundation. Genome-wide genotyping and collaborative scientific support was provided by Amgen.

Genotyping in the Genetic Epidemiology of Migraine Study was supported by the Netherlands Organisation for Scientific Research (NWO) VICI (918.56.602) and Spinoza (2009) grants and the Center for Medical Systems Biology (CMSB) established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO), project no. 050-060-409. The GEM study was supported by the Ministry of Health, Welfare and Sport and the National Institute of Public Health and the Environment, The Netherlands.

SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to the contribution of A. Teumer, A. Hoffmann and A. Petersmann in generating the SNP data. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of Siemens AG.

The IHGC study was supported, among others, by the Academy of Finland (200923 to A.P.), the Wellcome Trust (grant number 089062), the European Community's Seventh Framework Programme (FP7/2007-2013) (through the SYNSYS Consortium (grant agreement no. 242167) and the ENGAGE Consortium (grant agreement no. 201413)), the Helsinki University Central Hospital (to M.K.) and the Finnish Culture Foundation (to V.A.). Funding by the German Federal Ministry of Education and Research (BMBF) within the National Genome Research Network (NGFNplus, EMINet-01GS08120 for C.K., 01GS08121 to M. Dichgans), the Deutsche Forschungsgemeinschaft (to C.K.) and the Center for Molecular Medicine Cologne (to C.K.). For a full list of acknowledgements, please see reference 5.

Author information

Author notes

  1. Verneri Anttila, Mikko Kallela, Tobias Freilinger, Christian Kubisch and Aarno Palotie: On behalf of the International Headache Genetics Consortium (IHGC) (full list of consortium members appears in the Supplementary Note).

  2. Daniel I Chasman and Markus Schürks: These authors contributed equally to this work.

  3. Robert Y L Zee and Tobias Kurth: These authors jointly directed this work.

Authors and Affiliations

  1. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Daniel I Chasman, Markus Schürks, Julie E Buring, Paul M Ridker, Robert Y L Zee & Tobias Kurth

  2. Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Daniel I Chasman & Paul M Ridker

  3. Department of Neurology, University Hospital Essen, Essen, Germany

    Markus Schürks

  4. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Verneri Anttila & Aarno Palotie

  5. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    Verneri Anttila & Aarno Palotie

  6. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands

    Boukje de Vries & Arn M J M van den Maagdenberg

  7. Department of Neurology, Ernst-Moritz-Arndt University, Greifswald, Germany

    Ulf Schminke

  8. National Institute of Aging, Laboratory for Epidemiology, Demography, and Biometry, Bethesda, Maryland, USA

    Lenore J Launer

  9. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

    Gisela M Terwindt, Arn M J M van den Maagdenberg & Michel D Ferrari

  10. Institute for Community Medicine, Section Epidemiology of Health Care and Community Health, Ernst-Moritz-Arndt University, Greifswald, Germany

    Konstanze Fendrich & Wolfgang Hoffmann

  11. Institute for Community Medicine, Section Clinical Epidemiological Research, Ernst-Moritz-Arndt University, Greifswald, Germany

    Henry Völzke

  12. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University, Greifswald, Germany

    Florian Ernst

  13. Genomics Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Queensland, Australia

    Lyn R Griffiths

  14. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

    Mikko Kallela

  15. Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität and Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany

    Tobias Freilinger

  16. Institute of Human Genetics, University of Ulm, Ulm, Germany

    Christian Kubisch

  17. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Aarno Palotie

  18. Department of Medical Genetics, Helsinki University Central Hospital, Helsinki, Finland

    Aarno Palotie

  19. The Broad Institute of MIT and Harvard, Boston, Massachusetts, USA

    Aarno Palotie

  20. INSERM Unit 708—Neuroepidemiology, Paris, France

    Tobias Kurth

  21. UPMC Univ Paris 06, Paris, F-75005, France

    Tobias Kurth

Authors
  1. Daniel I Chasman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Schürks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Verneri Anttila
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Boukje de Vries
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulf Schminke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lenore J Launer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gisela M Terwindt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arn M J M van den Maagdenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Konstanze Fendrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Henry Völzke
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Florian Ernst
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lyn R Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Julie E Buring
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mikko Kallela
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tobias Freilinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christian Kubisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Paul M Ridker
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Aarno Palotie
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Michel D Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Wolfgang Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Robert Y L Zee
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Tobias Kurth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Obtained funding: J.E.B., M.D.F., W.H., T.K., A.M.J.M.v.d.M., A.P., P.M.R., U.S., H.V., R.Y.L.Z. Overall study design: D.I.C., T.K., M.S. Cohort supervision and phenotyping: V.A., J.E.B., K.F., M.D.F., T.F., W.H., M.K., C.K., T.K., L.J.L., A.P., P.M.R., U.S., M.S., G.M.T., H.V. Analysis and genotyping: V.A., D.I.C., K.F., L.R.G., W.H., A.M.J.M.v.d.M., P.M.R., U.S., M.S., F.E., B.d.V., R.Y.L.Z. Manuscript writing: D.I.C., M.S. All authors participated in critical review of the manuscript for intellectual content.

Corresponding authors

Correspondence to Markus Schürks or Tobias Kurth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1 and 2. (PDF 192 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chasman, D., Schürks, M., Anttila, V. et al. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 43, 695–698 (2011). https://doi.org/10.1038/ng.856

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.856

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing