Genetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt/β-catenin signalling in...

Migraine is a common complex disorder with a significant polygenic SNP heritability ([Formula: see text]). Here we utilise genome-wide association study (GWAS) summary statistics to study pleiotropy between blood proteins and migraine under the polygenic model. We estimate [Formula: see text] for 4625 blood protein GWASs and identify 325 unique proteins with a significant [Formula: see text] for use in subsequent genetic analyses. Pleiotropy analyses link 58 blood proteins to migraine risk at genome-wide, gene and/or single-nucleotide polymorphism levels-suggesting shared genetic influences or causal relationships. Notably, the identified proteins are largely distinct from migraine GWAS loci. We show that higher levels of DKK1 and PDGFB, and lower levels of FARS2, GSTA4 and CHIC2 proteins have a significant causal effect on migraine. The risk-increasing effect of DKK1 is particularly interesting-indicating a role for downregulation of β-catenin-dependent Wnt signalling in migraine risk, suggesting Wnt activators that restore Wnt/β-catenin signalling in brain could represent therapeutic tools against migraine.