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Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

A Corrigendum to this article was published on 28 September 2016

This article has been updated

Abstract

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

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Figure 1: Manhattan plot showing results of the primary meta-analysis of all migraine samples (59,674 case and 316,078 control).
Figure 2: Expression enrichment of genes from the migraine loci in GTEx tissue samples.
Figure 3: Expression enrichment of genes from the migraine loci in 209 tissue or cell type annotations by DEPICT.
Figure 4: Enrichment of the migraine loci in sets of tissue- and cell-type-specific enhancers.
Figure 5: DEPICT network of the reconstituted gene sets that were significantly enriched (FDR < 0.05, determined empirically by permutation) for genes at the migraine loci (Online Methods).

Change history

  • 18 July 2016

    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.

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Acknowledgements

We thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping, and genotyping for each of the individual cohorts. We also acknowledge the important contribution to research made by the study participants. We are grateful to H. Zhao (QIMR Berghofer Medical Research Institute) for helpful correspondence on the pathway analyses. We acknowledge the GTEx Consortium for support and contribution of pilot data. A list of study-specific acknowledgments and funding information can be found in the Supplementary Note.

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P.G., V. Anttila, G.W.M., M.I.K., M. Kals, R. Mägi, K.P., E.H., E.L., A.G.U., L.C., E.M., L.M., A.-L.E., A.F.C., T.F.H., A.J.A., D.I.C., and D.R.N. performed the experiments. P.G., V. Anttila, B.S.W., P.P., T.E., T.H.P., K.-H.F., M. Muona, N.A.F., A.I., G.M., L.L., S.G.G., S. Steinberg, L.Q., H.H.H.A., D.A.H., J.-J.H., R. Malik, A.E.B., E.S., C.M.v.D., E.M., D.P.S., N.E., B.M.N., D.I.C., and D.R.N. performed the statistical analyses. P.G., V. Anttila, B.S.W., P.P., T.E., T.H.P., K.-H.F., E.C.-L., N.A.F., A.I., G.M., L.L., M. Kallela, T.M.F., S.G.G., S. Steinberg, M. Koiranen, L.Q., H.H.H.A., T.L., J.W., D.A.H., S.M.R., M.F., V. Artto, M. Kaunisto, S.V., R. Malik, M.I.K., M. Kals, R. Mägi, K.P., H.H., A.E.B., J.H., E.S., C.S., C.W., Z.C., K.H., E.L., L.M.P., A.-L.E., A.F.C., T.F.H., J.K., A.J.A., O.R., M.A.I., M.-R.J., D.P.S., M.W., G.D.S., N.E., M.J.D., B.M.N., J.O., D.I.C., D.R.N., and A.P. participated in data analysis and/or interpretation. P.G., V. Anttila, B.S.W., T.H.P., K.-H.F., E.C.-L., T.K., G.M.T., M. Kallela, C.R., A.H.S., G.B., M. Koiranen, T.L., M.S., M.G.H., M.F., V. Artto, M. Kaunisto, S.V., R. Malik, A.C.H., P.A.F.M., N.G.M., G.W.M., H.H., A.E.B., L.F., J.H., P.H.L., C.S., C.W., Z.C., B.M.-M., S. Schreiber, T.M., J.G.E., V.S., A.G.U., C.M.v.D., A.S., C.S.N., H.G., A.-L.E., A.F.C., T.F.H., T.W., A.J.A., O.R., M.-R.J., C.K., M.D.F., A.C.B., M.D., M.W., J.-A.Z., B.M.N., J.O., D.I.C., D.R.N., A.-P.S., J.E.B., P.M.R., and A.P. contributed materials and/or analysis tools. T.E., T.K., T.L., H.S., B.W.J.H.P., A.C.H., P.A.F.M., N.G.M., G.W.M., L.F., A.H., A.S., C.S.N., M. Männikkö, T.W., J.K., O.R., M.A.I., T.S., M.-R.J., A.M., C.K., D.P.S., M.D.F., A.M.J.M.v.d.M., J.-A.Z., D.I.B., G.D.S., K.S., N.E., B.M.N., J.O., D.I.C., D.R.N., and A.P. supervised the research. T.K., G.M.T., G.B., T.L., J.E.B., M.S., P.M.R., H.S., B.W.J.H.P., A.C.H., P.A.F.M., N.G.M., G.W.M., L.F., V.S., A.H., L.C., A.S., C.S.N., H.G., J.K., A.J.A., O.R., M.A.I., M.-R.J., A.M., C.K., D.P.S., M.D., A.M.J.M.v.d.M., D.I.B., G.D.S., N.E., M.J.D., B.M.N., D.I.C., D.R.N., and A.P. conceived and designed the study. P.G., V. Anttila, B.S.W., P.P., T.E., T.H.P., E.C.-L., H.H., B.M.N., J.O., D.I.C., D.R.N., and A.P. wrote the paper. All authors contributed to the final version of the manuscript.

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Correspondence to Aarno Palotie.

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Competing interests

T.W. has acted as a lecturer and consultant for H. Lundbeck A/S, Valby, Denmark. M.S. is a full-time employee of Bayer HealthCare, Germany.

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A full list of members and affiliations appears at the end of the paper and in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 3–15, and Supplementary Tables 1–25 (PDF 7376 kb)

Supplementary Figure 1

Forest plots of the 44 independently associated SNPs (PDF 2623 kb)

Supplementary Figure 2

Regional plots of the 44 independently associated SNPs (PDF 3517 kb)

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Gormley, P., Anttila, V., Winsvold, B. et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 48, 856–866 (2016). https://doi.org/10.1038/ng.3598

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