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

Background: Erectile dysfunction (ED) is a common condition affecting millions of men worldwide. While genome-wide association studies (GWAS) have identified genetic loci associated with ED risk, the potential causative genes and their biological mechanisms leading to ED remain largely unexplored.

Objective: This study aimed to conduct a comprehensive cross-tissue transcriptome-wide association study (TWAS) to identify susceptibility genes associated with ED risk.

Methods: We conducted a cross-tissue TWAS analysis integrating GWAS data for ED with eQTL files from Genotype-Tissue Expression Project (GTEx) V8. We used the unified test for molecular signatures (UTMOST) for cross-tissue analysis and functional summary-based imputation (FUSION) for single-tissue validation. Candidate genes were further validated through multi-marker analysis of genomic annotation (MAGMA), conditional and joint (COJO) analysis, and colocalization analysis.

Results: The cross-tissue TWAS analysis identified 118 significant genes associated with ED, while the single-tissue TWAS validation revealed 3804 significant genes. Nine candidate genes (CPT1B, CSF2RB, DNAH7, EHD3, L3MBTL2, LCLAT1, MDH1B, REEP1, and SLC30A6) were consistently identified across the TWAS and MAGMA analyses. COJO analysis revealed that LCLAT1 accounted for most of the signals at their respective loci. Colocalization analysis confirmed LCLAT1 as the primary candidate gene, showing strong colocalization with ED in testis, brain cortex, and heart left ventricle.

Conclusions: This comprehensive cross-tissue TWAS analysis identified LCLAT1 as a primary susceptibility gene for ED, highlighting its potential role in the mitochondrial function and lipid metabolism. The study also revealed several secondary candidate genes that may contribute to ED through pathways related to mitochondrial dynamics, neurotransmission, and cardiovascular function. These findings provide new perspectives on the genetic architecture of ED and suggest potential targets for future research and treatment.