Integrating genomic structural equation modeling and experimental validation to unravel the genetic basis of male genital lichen sclerosus - Summary - MDSpire
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Integrating genomic structural equation modeling and experimental validation to unravel the genetic basis of male genital lichen sclerosus
To investigate the genetic architecture of male genital lichen sclerosus (MGLSc) and identify potential susceptibility loci, candidate genes, and biological pathways associated with disease pathogenesis.
Approach:
Genomic-SEM Framework: Integrated publicly available GWAS summary statistics to construct a Genomic-SEM framework and estimate genetic correlations.
Functional Mapping: Performed functional mapping and annotation using FUMA, and screened novel loci through a GWAS subtraction strategy.
Fine-Mapping: Conducted fine-mapping using SuSIE and FINEMAP to prioritize candidate causal variants.
Transcriptome-Wide Association Study: Applied TWAS and FOCUS to identify candidate genes.
Biological Relevance Analysis: Performed MAGMA-based gene enrichment, partitioned heritability analysis, and polygenic risk score analyses.
Experimental Validation: Conducted RT-qPCR to validate the expression of prioritized genes.
Key Findings:
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Interpretation:
MGLSc is influenced by a shared polygenic architecture enriched in immune-related loci, particularly within the HLA region.
Limitations:
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Conclusion:
The study provides insights into the genetic basis of MGLSc, identifying HLA-DPA1 as a high-confidence susceptibility gene and multiple novel loci and candidate genes.
