SUPPLEMENTARY INFORMATION Table of Contents Supplementary Methods ........................................................................................................ 3 Study Design .................................................................................................................................................................................. 3 Description of population-based studies ............................................................................................................................. 4 Description of clinic-based studies ..................................................................................................................................... 17 Study-specific acknowledgements ...................................................................................................................................... 20 Ethics Statement ....................................................................................................................................................................... 25 Conflicts of Interest ................................................................................................................................................................ 25 Study Phenotypes ..................................................................................................................................................................... 25 Quality Control ........................................................................................................................................................................... 25 Imputation ................................................................................................................................................................................... 26 Statistical Analysis ..................................................................................................................................................................... 26 Chromosome X meta-analysis .............................................................................................................................................. 27 Defining Credible Sets ............................................................................................................................................................. 27 eQTL CrediBle Set Overlap Analysis .................................................................................................................................... 29 eQTL Conditional Analysis ...................................................................................................................................................... 30 Enhancer Enrichment Analysis ............................................................................................................................................. 31 DEPICT gene-set enrichment ................................................................................................................................................ 32 GTEx tissue expression enrichment analysis. .................................................................................................................. 34 Supplementary References ................................................................................................... 35 Supplementary Figures ......................................................................................................... 41 Supplementary Figure 1. Region plots of the 38 genome-wide significant loci (see separate attached PDF document for figure). .............................................................................................................................................................. 41 Supplementary Figure 2. Individual gene expression in tissues from GTEx. ........................................................ 42 Supplementary Figure 3. QQ-plot of the primary analysis test statistics. ............................................................. 43 Supplementary Figure 4. QQ-plot of the primary analysis after LD-pruning. ...................................................... 44 Supplementary Figure 5. LD-score regression plot for all migraine. ....................................................................... 45 Supplementary Figure 6. LD-score regression plot for the MA suBtype. ............................................................... 46 Supplementary Figure 7. LD-score regression plot for the MO suBtype. .............................................................. 47 Supplementary Figure 8. Manhattan plot for the MO suBtype. ............................................................................... 48 Supplementary Figure 9. Manhattan plot for the MA suBtype. ............................................................................... 49 Supplementary Figure 10. Correlation of test statistics Between migraine and eQTL SNPs at the MRVI1 locus. ............................................................................................................................................................................................. 50 Supplementary Figure 11. Gene expression of the 38 genes nearest to the migraine loci index SNPs. ..... 51 Supplementary Figure 12. Gene expression of TGFBR2 in 60 different types of smooth muscle tissue. ... 52 Supplementary Figure 13. Gene expression of NRP1 in 60 different types of smooth muscle tissue. ....... 53 Supplementary Tables .......................................................................................................... 54 Supplementary Table 1. Design and characteristics of IHGC individual GWA studies. ..................................... 54 Supplementary Table 2. QC and imputation description of the individual GWA studies. ............................... 56 Supplementary Table 3. Previously reported loci not reaching genome-wide significance in the current meta-analysis. ............................................................................................................................................................................ 59 1 Supplementary Table 4. The 45 LD-independent SNPs that reached genome-wide significance in the primary meta-analysis of all migraine. .............................................................................................................................. 60 Supplementary Table 5. Overlaps with the NHGRI GWAS catalog and OMIM of all 38 loci identified, rank ordered by lowest p-value of association. ....................................................................................................................... 62 Supplementary Table 6. Genes in the 38 loci with previously reported associations to mechanisms or diseases that have hypothesized links to migraine. ...................................................................................................... 67 Supplementary Table 7. The two suBsets of non-overlapping MA/MO samples meta-analyzed to compare heterogeneity in the migraine subtypes. ....................................................................................................... 68 Supplementary Table 8. Testing for heterogeneity Between MA and MO at the 45 independent SNPs associated to all migraine in the primary analysis. ........................................................................................................ 69 Supplementary Table 9. CrediBle-set genic overlap analysis. ................................................................................... 71 Supplementary Table 10. Conditional analysis of the migraine index SNPs adjusted for the signal of the most significant local cis-eQTL SNP in Estonian peripheral Blood data. ................................................................ 73 Supplementary Table 11. Overlap of the migraine and eQTL crediBle sets in gene expression data from peripheral blood. ....................................................................................................................................................................... 74 Supplementary Table 12. Overlap of the migraine and eQTL crediBle sets in gene expression data from brain tissues ................................................................................................................................................................................ 75 Supplementary Table 13. DEPICT gene-expression enrichment in specific tissues. .......................................... 76 Supplementary Table 14. Gene Ontology over-representation analysis of the nearest genes to the 38 migraine loci. .............................................................................................................................................................................. 87 Supplementary Table 15. Selected pathways from the DEPICT analysis that have a previously hypothesized role in migraine. ............................................................................................................................................. 88 Supplementary Table 16. DEPICT reconstituted gene sets that were significantly enriched for genes within the 38 migraine loci at FDR < 5%. .......................................................................................................................... 89 2 Supplementary Methods Study Design We jointly analyzed the summary statistics from 22 genome-wide association (GWA) studies provided by collaborators in the International Headache Genetics Consortium. The 22 population-matched GWA studies