8 CHAPTER 8 176 categories (Methods) in the GWAS Catalog, and 17 lead variants with 26 defined disease categories in FinnGen at P < 1 × 10-5. The categories with the highest number of reported associations were cardiovascular disease (7 lead variants) and blood pressure (6 lead variants) in the GWAS Catalog, and diseases of the circulatory system (11 lead variants) in FinnGen. When we performed PheWAS for all variants in high LD (r2 > 0.6) with the lead variants, we observed associations for 79 loci with 54 different phenotype categories in the GWAS Catalog, and for 41 loci with 26 disease categories in FinnGen (Supplementary Table 13A and Supplementary Figure 6). These findings are consistent with previous results that migraine is a risk factor for multiple cardiovascular traits74-76, and genetically correlated with blood pressure.77, 78 However, we did not observe a trend in the direction of the allelic effects between migraine and coronary artery disease (CAD) or migraine and blood pressure traits (Supplementary Table 13D) using the latest metaanalysis of CARDIoGRAMplusCD4 Consortium59 (n = 336,924) and blood pressure GWAS from UK Biobank60 (n = 422,771). Enrichment in tissue or cell types and gene sets. We used LDSC applied to specifically expressed genes (LDSC-SEG)14 (Methods) to evaluate whether the polygenic migraine signal was enriched near genes that were particularly active in certain tissue or cell types as determined by gene expression or activating histone marks. Using multi-tissue gene expression data, we found enrichment at FDR 5% in three cardiovascular tissue/cell types, i.e., aorta artery (P = 1.78 × 10-4), tibial artery (P = 3.60 × 10-4) and coronary artery (P = 4.29 × 10-4) (Table 3 and Supplementary Table 14A), all of which have previously been reported enriched in migraine without aura.14 The fine-scale brain expression data from GTEx, since recently including 13 brain regions, showed enrichment in the caudate nucleus of striatum, a component of basal ganglia (P = 6.02 × 10-4; Table 3 and Supplementary Table 14B). With chromatin-based annotations, we found enrichment in five central nervous system (CNS) cell types, three cardiovascular cell types, one cell type of the digestive system, one musculoskeletal/connective cell type, and ovary tissue (Table 3 and Supplementary Table 14C). In addition to replicating previous findings,13, 14 the signal linking to ovary tissue has not been reported before. Finally, we used DEPICT64 to identify tissues whose eQTLs were enriched for migraineassociated variants. The tissue enrichment analysis replicated three previously reported tissues13: arteries (nominal P = 1.03 × 10-3), stomach (nominal P = 1.04 × 10-3) and upper gastrointestinal tract (nominal P = 1.29 × 10-3) (Supplementary Table 14A). Results of gene set analyses using DEPICT64 and MAGMA61 are presented in Supplementary Tables 15 and 16.
RkJQdWJsaXNoZXIy MTk4NDMw