School of Biomedical Sciences, Faculty of Health, and Centre for Genomics and Personalised Health, Queensland University of Technology (QUT), Brisbane, QLD, Australia.
Nat Commun. 2022 May 11;13(1):2593. doi: 10.1038/s41467-022-30184-z.
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.
偏头痛是一种常见的复杂疾病，具有显著的多基因 SNP 遗传力 ([公式：见正文])。在这里，我们利用全基因组关联研究 (GWAS) 汇总统计数据，在多基因模型下研究血液蛋白与偏头痛之间的多效性。我们估计了 4625 个血液蛋白 GWAS 的 [公式：见正文]，并确定了 325 个具有显著 [公式：见正文] 的独特蛋白质，可用于随后的遗传分析。多效性分析将 58 种血液蛋白与全基因组、基因和/或单核苷酸多态性水平的偏头痛风险联系起来，表明存在共同的遗传影响或因果关系。值得注意的是，所鉴定的蛋白质与偏头痛 GWAS 基因座有很大的不同。我们表明，DKK1 和 PDGFB 水平升高，FARS2、GSTA4 和 CHIC2 蛋白水平降低与偏头痛风险有显著的因果关系。DKK1 的风险增加效应特别有趣，表明β-连环蛋白依赖性 Wnt 信号下调在偏头痛风险中的作用，提示恢复脑内 Wnt/β-连环蛋白信号的 Wnt 激活剂可能成为治疗偏头痛的工具。
