Fine-mapping a genome-wide meta-analysis of 98,374 migraine cases identifies 181 sets of candidate causal variants
Abstract
Migraine is a highly prevalent neurovascular disorder for which genome-wide association studies (GWAS) have identified over one hundred risk loci, yet the causal variants and genes remain mostly unknown. Here, we meta-analyze three migraine GWAS including 98,374 cases and 869,160 controls and identify 122 independent risk loci of which 35 were new. Fine-mapping of a meta-analysis is challenging because some variants may be missing from some participating studies and accurate linkage disequilibrium (LD) information of the variants is often not available. Here, using the exact in-sample LD, we first investigate which statistics could reliably capture the quality of fine-mapping when only reference LD is available. We observe that the posterior expected number of causal variants best distinguishes between the high- and low-quality results. Next, we perform fine-mapping for 102 autosomal risk regions using FINEMAP. We produce high-quality fine-mapping for 93 regions and define 181 distinct credible sets. Among the high-quality credible sets are 7 variants with very high posterior inclusion probability (PIP > 0.9) and 2 missense variants with PIP > 0.5 (rs6330 in NGF and rs1133400 in INPP5A). For 35 association signals, we manage to narrow down the set of potential risk variants to at most 5 variants. A large-scale migraine genetics study identifies 122 risk regions, including 35 previously unreported ones, and pinpoints likely causal genetic variants using an in silico…
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