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-analyzed three migraine GWAS including 98,374 cases and 869,160 controls and identified 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 investigated which statistics could reliably capture the quality of fine-mapping when only reference LD was available. We observed that the posterior expected number of causal variants best distinguished between the high- and low-quality results. Next, we performed fine-mapping for 102 autosomal risk regions using FINEMAP. We produced high-quality fine-mapping for 93 regions and defined 181 distinct credible sets. Among the high-quality credible sets were 7 variants with very high posterior inclusion probability (PIP > 0.9) and 2 missense variants with PIP > 0.5 (rs6330 inNGFand rs1133400 inINPP5A). For 35 association signals, we managed to narrow down the set of potential risk variants to at most 5 variants.