biostudies-literatureUnknown8(3)Zhang L<h4>Background</h4>Intervertebral disc degeneration (IDD) is a prevalent spinal condition frequently associated with pain and motor impairment, imposing a substantial burden on quality of life. Despite extensive investigations into the genetic predisposition to IDD, the precise pathogenic genes and molecular pathways involved remain inadequately characterized, underscoring the need for continued research to clarify its genetic underpinnings.<h4>Methods</h4>This study leveraged IDD data from the FinnGen R12 cohort and integrated expression quantitative trait loci data across 49 tissues from the Genotype-Tissue Expression version 8 database to perform a cross-tissue transcriptome-wide association study (TWAS). The analytical framework incorporated functional summary-based imputation (FUSION), unified test for molecular signatures (UTMOST), and gene-level analysis via multi-marker genome annotation (MAGMA). To substantiate the findings, Mendelian randomization (MR) and colocalization analyses were subsequently conducted.<h4>Results</h4>Through TWAS and MAGMA analyses, 33 susceptibility genes associated with IDD were identified. Subsequent MR and colocalization analyses refined this list to six candidate genes-ADD1, GFPT1, MAPRE3, MSANTD1, SLC30A6, and XBP1-which may contribute to the initiation and progression of IDD by modulating pathways implicated in the endoplasmic reticulum stress response.<h4>Conclusion</h4>Six susceptibility genes associated with the risk of IDD were identified in this study, offering novel insights into the genetic architecture and potential pathogenic pathways underpinning the development of IDD.JOR spinee70109https://www.ebi.ac.uk/biostudies/studies/S-EPMC12414482biostudies-literatureA Cross-Tissue Transcriptome-Wide Association Study Identified Susceptibility Genes for Intervertebral Disc Degeneration.PMC12414482Yang HDeng TLi YZhao WZhang LfalseA Cross-Tissue Transcriptome-Wide Association Study Identified Susceptibility Genes for Intervertebral Disc Degeneration.<h4>Background</h4>Intervertebral disc degeneration (IDD) is a prevalent spinal condition frequently associated with pain and motor impairment, imposing a substantial burden on quality of life. Despite extensive investigations into the genetic predisposition to IDD, the precise pathogenic genes and molecular pathways involved remain inadequately characterized, underscoring the need for continued research to clarify its genetic underpinnings.<h4>Methods</h4>This study leveraged IDD data from the FinnGen R12 cohort and integrated expression quantitative trait loci data across 49 tissues from the Genotype-Tissue Expression version 8 database to perform a cross-tissue transcriptome-wide association study (TWAS). The analytical framework incorporated functional summary-based imputation (FUSION), unified test for molecular signatures (UTMOST), and gene-level analysis via multi-marker genome annotation (MAGMA). To substantiate the findings, Mendelian randomization (MR) and colocalization analyses were subsequently conducted.<h4>Results</h4>Through TWAS and MAGMA analyses, 33 susceptibility genes associated with IDD were identified. Subsequent MR and colocalization analyses refined this list to six candidate genes-ADD1, GFPT1, MAPRE3, MSANTD1, SLC30A6, and XBP1-which may contribute to the initiation and progression of IDD by modulating pathways implicated in the endoplasmic reticulum stress response.<h4>Conclusion</h4>Six susceptibility genes associated with the risk of IDD were identified in this study, offering novel insights into the genetic architecture and potential pathogenic pathways underpinning the development of IDD.2025-01-01T00:00:00Z2025 Sep2026-06-02T22:34:18.656Z2026-05-28T03:06:29.887ZS-EPMC124144824092280710.1002/jsp2.70109