Identifying causal genes for migraine by integrating the proteome and transcriptome

Area of Science:

• Genetics
• Neuroscience
• Proteomics

Background:

• Genome-wide association studies (GWAS) have identified migraine risk variants, but their functional roles remain unclear.
• Understanding how genetic variants contribute to migraine pathogenesis is crucial for developing effective treatments.

Purpose of the Study:

• To identify causal genes for migraine by integrating genetic association data with proteomic and transcriptomic information.
• To uncover novel genes and pathways involved in migraine development.

Main Methods:

• Conducted a proteome-wide association study (PWAS) using migraine GWAS data and human brain/plasma proteomic data.
• Performed transcriptome-wide association studies (TWAS) with a joint-tissue imputation (JTI) model and fine-mapping (FOCUS) on 17 human tissues.
• Integrated PWAS and TWAS to identify genes modulating migraine risk through protein abundance and gene expression.

Main Results:

• Identified 13 genes in brain and plasma proteomes associated with migraine risk via protein abundance.
• Discovered 62 novel migraine-associated genes using TWAS and fine-mapping, not previously reported.
• Five genes (ICA1L, TREX1, STAT6, UFL1, B3GNT8) showed significant associations in both proteomic and transcriptomic analyses, primarily in ependymal cells, neurons, and glial cells.

Conclusions:

• The identified genes provide new insights into the pathogenesis of migraine.
• These findings highlight potential therapeutic targets for migraine prevention and treatment.