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

Migraine is a common complex disorder with a significant polygenic SNP heritability ( h S N P 2 ). Here we utilise genome-wide association study (GWAS) summary statistics to study pleiotropy between blood proteins and migraine under the polygenic model. We estimate h S N P 2 for 4625 blood protein G...

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Bibliographic Details
Published in:Nature communications 2022-05, Vol.13 (1), p.2593-2593, Article 2593
Main Authors: Tanha, Hamzeh M., Nyholt, Dale R.
Format: Article
Language:English
Subjects:
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Blood
Dkk1 protein
Gene polymorphism
Genetic analysis
Genetic effects
Genome-wide association studies
Genomes
Headache
Heritability
Humanities and Social Sciences
Loci
Migraine
multidisciplinary
Nucleotides
Pleiotropy
Polymorphism
Proteins
Risk
Science
Science (multidisciplinary)
Signaling
Single-nucleotide polymorphism
Wnt protein
β-Catenin
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Summary:Migraine is a common complex disorder with a significant polygenic SNP heritability ( h S N P 2 ). Here we utilise genome-wide association study (GWAS) summary statistics to study pleiotropy between blood proteins and migraine under the polygenic model. We estimate h S N P 2 for 4625 blood protein GWASs and identify 325 unique proteins with a significant h S N P 2 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. Understanding of the causes and treatment of migraine is incomplete. Here, the authors detect pleiotropic genetic effects and causal relationships between migraine and 58 proteins that are largely distinct from migraine-associated loci identified by GWAS.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-30184-z