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

Area of Science:

• Genetics
• Molecular Biology
• Urology

Background:

• Erectile dysfunction (ED) is a prevalent condition with millions affected globally.
• Genome-wide association studies (GWAS) have identified genetic loci for ED risk.
• Causative genes and biological mechanisms underlying ED remain largely unexplored.

Purpose of the Study:

• To conduct a comprehensive cross-tissue transcriptome-wide association study (TWAS) for ED.
• To identify novel susceptibility genes associated with erectile dysfunction risk.
• To elucidate the genetic architecture of ED.

Main Methods:

• Integrated GWAS data for ED with GTEx V8 eQTL data.
• Employed unified test for molecular signatures (UTMOST) for cross-tissue analysis.
• Validated candidate genes using FUSION, MAGMA, COJO, and colocalization analyses.

Main Results:

• Identified 118 significant genes via cross-tissue TWAS and 3804 via single-tissue TWAS.
• Consistently identified nine candidate genes, including LCLAT1, across TWAS and MAGMA.
• Confirmed LCLAT1 as the primary candidate gene through COJO and colocalization analyses in multiple tissues.

Conclusions:

• LCLAT1 is identified as a primary susceptibility gene for ED.
• LCLAT1's role in mitochondrial function and lipid metabolism is highlighted.
• Secondary candidate genes suggest pathways involving mitochondrial dynamics, neurotransmission, and cardiovascular function in ED.