8 CHAPTER 8 170 Transcriptome-wide association study and colocalization We performed a transcriptome-wide association study (TWAS) by S-PrediXcan65 v0.7.5 using GTEx v8 multivariate adaptive shrinkage models (MASHR-M) for 49 tissues downloaded from predictdb. org and the European 1000 Genomes v3 LD reference panel (hg38). We followed the recommended QC protocol, and first harmonized and imputed the migraine summary statistics to ensure an optimal overlap with the GTEx v8 expression weights. After the harmonization and summary statistic imputation, 8,909,736 variants were available for the TWAS. We performed the analysis with default settings to identify significant gene-tissue pairs. We applied a Bonferroni corrected significance level of α =0.05/662,726, corresponding to the number of unique gene-tissue pairs tested. Next, we performed colocalization analysis with COLOCv4.0.466 R package for the 1,844 significant gene-tissue pairs to indicate pairs that could be due to LD contamination. COLOC compares five hypotheses where the null hypothesis (H0) corresponds to no association to either eQTL or GWAS, H1 and H2 correspond to associations with only one of the traits, H3 corresponds to association with both eQTL and GWAS but at distinct causal variants, and H4 corresponds to association with both eQTL and GWAS at a shared causal variant. We set a prior probability for colocalization as p12 = 5 × 10 -6 for all tested regions and restricted the analysis to variants that had Neff ± 10% of the Neff of the lead variant of the region. Results are presented in Supplementary Table 11B. Fine-mapping of causal gene sets (FOCUS) To prioritize genes for the migraine loci, we applied a gene-based fine-mapping approach using FOCUS v0.7.67 FOCUS is a Bayesian approach that models predicted expression correlations among TWAS signals to estimate posterior probabilities for all genes within a tested region. We used the European 1000 Genomes v3 LD reference panel and same GTEx v8 predicted expression weights for the 49 tissues as with S-PrediXcan. First, we mapped the migraine summary statistics from hg37 to hg38 with UCSC liftOver.68 Next, we followed the suggested QC protocol and applied the modified munge-tool to obtain cleaned summary statistics. After the QC steps, we had 6,237,177 variants left for the analysis. We performed tissue-prioritized fine-mapping of genesets for the 49 tissues with otherwise default settings except that we increased the P-value threshold to 1 × 10-4 so that the fine-mapping would cover most of the same regions that contained at least one significant gene-tissue pair by S-PrediXcan. Posterior inclusion probability (PIP) from FOCUS is reported for all available significant S-PrediXcan gene-tissue pairs in Supplementary Table 11B, and all prioritized genes by FOCUS with PIP > 0.9 are reported in Supplementary Table 11A. Data Availability Results for 8,117 genome-wide significant SNP associations (P < 5 × 10-8) from the meta-analysis including 23andMe data are available on the International Headache Genetics Consortium website (http://www.headachegenetics.org/content/datasets-and-cohorts). Genome-wide summary
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