GENOME-WIDE ANALYSIS OF 102,084 MIGRAINE CASES IDENTIFIES 123 RISK LOCI AND SUBTYPE-SPECIFIC RISK ALLELES 175 8 Two of the new risk loci contain genes (CALCA/CALCB and HTR1F) whose protein products are closely related to targets of two migraine-specific drug therapies.73 We observe a convincing association at the chromosome 11 locus that contains the CALCA and CALCB genes encoding CGRP itself (lead SNP rs1003194, P = 2.43 × 10-10; Figure 2A), while none of the genes encoding CGRP receptor proteins (CALCRL, RAMP1 or RCP) show a statistically comparable association (all P > 10-4; Supplementary Figure 5). Variant rs1003194 is a cis-eQTL for CALCB, but also for COPB1, PDE3B and INSC (Supplementary Table 9) and FOCUS prioritizes CALCA, CALCB and INSC (Supplementary Table 11C). In addition, a new locus on chromosome 3 contains HTR1F (lead SNP rs6795209, P = 1.23 × 10-8; Figure 2B), which encodes the serotonin 5-HT 1F receptor. Variant rs6795209 is a significant cis-eQTL for HTR1F, as well as for three other genes (CGGBP1, ZNF654, C3orf38) in the same locus (Supplementary Table 9). FOCUS or S-PrediXcan + COLOC did not prioritize HTR1F based on gene expression data (Supplementary Table 11C). Migraine subtypes with aura and without aura Previously, Gormley et al.13 conducted subtype-specific GWAS with 6,332 MA cases against 144,883 controls and 8,348 MO cases against 139,622 controls, and reported that 7 loci were GWS in MO but none were GWS in MA. Here we added to the previous data 8,292 new MA and 6,707 new MO cases from headache specialist centers in Denmark and the Netherlands as well as from study collections in Iceland and UK Biobank (Table 2), for total sample sizes of 14,624 MA cases and 703,852 controls, and 15,055 MO cases and 682,301 controls. We estimated the effect size for each subtype at the 123 lead variants of the migraine GWAS (Supplementary Table 3B,C and Supplementary Data 4 and 5) and detected four GWS variants in the MA meta-analysis and 15 GWS variants in the MO meta-analysis. We also estimated a probability that the lead variant is either subtype-specific (i.e., associated only with MO or with MA but not with both), shared by both subtypes, or not associated with either subtype (Methods, Supplementary Table 12A, and Supplementary Data 6). With a probability above 95%, three lead variants (i.e., rs12598836 in the HMOX2 locus, rs10405121 in the CACNA1A locus, and rs11031122 in the MPPED2 locus) are MA-specific, while two lead variants (i.e., rs7684253 in the locus near SPINK2 and rs8087942 in the locus near FECH) are MO-specific at a similar threshold. Nine lead variants were shared by MA and MO with > 95% probability (Figure 3A). In addition to the five subtype-specific lead variants, four other lead variants also showed differences in effect size between the subtypes (P < 0.05/123) (Figure 3B). PheWAS with NHGRI GWAS Catalog and FinnGen R4 Next, we conducted phenome-wide association scans (PheWAS) for the lead variants for 4,314 traits with reported associations in the NHGRI GWAS Catalog (https://www.ebi.ac.uk/gwas/) and for the GWAS summary statistics of 2,263 disease traits in the FinnGen release 4 data. We identified 25 lead variants that were reported to be associated with 23 different phenotype
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