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. 2024 Jun 5;25(1):94.
doi: 10.1186/s10194-024-01802-6.

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

Jianxiong Gui #  1 , Xiaoyue Yang #  1 , Chen Tan  1 , Lingman Wang  1 , Linxue Meng  1 , Ziyao Han  1 , Jie Liu  2 , Li Jiang  3
Affiliations

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

Jianxiong Gui et al. J Headache Pain. .

Abstract

Background: Migraine is a common neurological disorder with a strong genetic component. Despite the identification of over 100 loci associated with migraine susceptibility through genome-wide association studies (GWAS), the underlying causative genes and biological mechanisms remain predominantly elusive.

Methods: The FinnGen R10 dataset, consisting of 333,711 subjects (20,908 cases and 312,803 controls), was utilized in conjunction with the Genotype-Tissue Expression Project (GTEx) v8 EQTls files to conduct cross-tissue transcriptome association studies (TWAS). Functional Summary-based Imputation (FUSION) was employed to validate these findings in single tissues. Additionally, candidate susceptibility genes were screened using Gene Analysis combined with Multi-marker Analysis of Genomic Annotation (MAGMA). Subsequent Mendelian randomization (MR) and colocalization analyses were conducted. Furthermore, GeneMANIA analysis was employed to enhance our understanding of the functional implications of these susceptibility genes.

Results: We identified a total of 19 susceptibility genes associated with migraine in the cross-tissue TWAS analysis. Two novel susceptibility genes, REV1 and SREBF2, were validated through both single tissue TWAS and MAGMA analysis. Mendelian randomization and colocalization analyses further confirmed these findings. REV1 may reduce the migraine risk by regulating DNA damage repair, while SREBF2 may increase the risk of migraine by regulating cholesterol metabolism.

Conclusion: Our study identified two novel genes whose predicted expression was associated with the risk of migraine, providing new insights into the genetic framework of migraine.

Keywords: Colocalization; Cross-tissue TWAS; Mendelian randomization; Migraine; UTMOST.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The flowchart of this study. GWAS, genome-wide association; GTEx, Genotype-Tissues Expression Project; TWAS, transcriptome-wide association studies; UTMOST, unified test for molecular signatures; FUSION, functional summary-based imputation; MAGMA, multi-marker Analysis of GenoMic Annotation
Fig. 2
Fig. 2
Venn diagram. MAGMA identified 89 significant genes associated with hypertension, FUSION identified 144, and UTMOST cross-tissue analysis identified 19, of which 2 were common
Fig. 3
Fig. 3
The results of colocalization analysis between candidate genes and migraine. The SNP rs17022564 exhibited the lowest cumulative sum of migraine GWAS and REV1 eQTL p values both in Whole_Blood (A) and Cells_Cultured_fibroblasts (B). The SNP rs738248 exhibited the lowest cumulative sum of migraine GWAS and SREBF2 eQTL p values both in Skin_Sun_Exposed_Lower_leg (C) and Testis (D)
Fig. 4
Fig. 4
The MR results confirmed the causal associations between two candidate genes and migraine
Fig. 5
Fig. 5
GeneMania gene network. (A)REV1 as the core, and (B)SREBF2 as the core
See this image and copyright information in PMC

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