Integrating eQTL and GWAS data characterises established and identifies novel migraine risk loci

Abstract

Migraine—a painful, throbbing headache disorder—is the most common complex brain disorder, yet its molecular mechanisms remain unclear. Genome-wide association studies (GWAS) have proven successful in identifying migraine risk loci; however, much work remains to identify the causal variants and genes. In this paper, we compared three transcriptome-wide association study (TWAS) imputation models—MASHR, elastic net, and SMultiXcan—to characterise established genome-wide significant (GWS) migraine GWAS risk loci, and to identify putative novel migraine risk gene loci. We compared the standard TWAS approach of analysing 49 GTEx tissues with Bonferroni correction for testing all genes present across all tissues (Bonferroni), to TWAS in five tissues estimated to be relevant to migraine, and TWAS with Bonferroni correction that took into account the correlation between eQTLs within each tissue (Bonferroni-matSpD). Elastic net models performed in all 49 GTEx tissues using Bonferroni-matSpD characterised the highest number of established migraine GWAS risk loci (n = 20) with GWS TWAS genes having colocalisation (PP4 > 0.5) with an eQTL. SMultiXcan in all 49 GTEx tissues identified the highest number of putative novel migraine risk genes (n = 28) with GWS differential expression at 20 non-GWS GWAS loci. Nine of these putative novel migraine risk genes were later found to be at and in linkage disequilibrium with true (GWS) migraine risk loci in a recent, more powerful migraine GWAS. Across all TWAS approaches, a total of 62 putative novel migraine risk genes were identified at 32 independent genomic loci. Of these 32 loci, 21 were true risk loci in the recent, more powerful migraine GWAS. Our results provide important guidance on the selection, use, and utility of imputation-based TWAS approaches to characterise established GWAS risk loci and identify novel risk gene loci.

A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for migraine

“…However, this emphasizes the significance of conducting multiple avenues of research to identify potential genetic factors contributing to migraine susceptibility. To a certain extent, both of these studies incorporated cross-tissue TWAS analysis [ 32 , 33 ]; however, it is imperative to further validate the outcomes of the cross-tissue analysis, as their primary focus remained on investigating the association between genes in single tissue and migraine. Moreover, in comparison to GTEx V7, the updated version V8 encompasses a 49% increase in RNA-seq samples derived from 33% more tissue donors, alongside the inclusion of splicing eQTLs [ 34 ].…”

“…Li et al identified five genes associated with migraine in human brain tissue and plasma proteomic and transcriptomic analyses, which are mainly expressed in ependymal cells, neurons, and glial cells [23]. Another study utilized imputation models of three TWAS, MASHR, elastic net, and SMultiXcan to identify risk loci for migraine GWAS and potential susceptibility genes [32]. Meyers et al also employed a TWAS analysis, utilizing eQTL data from GTEx V7, to identify novel candidate susceptibility genes associated with migraine [33].…”

“…Current hypotheses propose that vascular function, metal ion homeostasis, neuronal function, and ion channel activity may be implicated in the pathophysiology of migraine; nevertheless, these notions still necessitate validation through high-throughput experiments conducted on cellular and animal models [51]. We sought to explore the potential interactions among SREBF2 or REV1 and previously identified genes associated with migraine susceptibility [8,23,32,33,[50][51][52][53]. However, substantial evidence is currently lacking.…”

Unraveling the migraine origin: is it genetics or environmental?

“… 4 Genome-wide association studies (GWAS) have been identifying migraine risk loci, a recent analysis of three different imputation models showed a total of 62 putative novel migraine risk genes identifed at 32 independent genomic loci. 5 This evidence suggests the multifactorial nature of migraine.…”