A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen Cohort
<b>Background/Objectives</b>: Diabetic kidney disease (DKD) is a common diabetic complication, driven by a multifactorial pathogenesis that includes various genetic components. However, the precise causative genes and their underlying biological pathways remain poorly understood. <b&g...
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MDPI AG
2025-05-01
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| author | Menghan Liu Zehua Li Yao Lu Pingping Sun Ying Chen Li Yang |
| author_facet | Menghan Liu Zehua Li Yao Lu Pingping Sun Ying Chen Li Yang |
| author_sort | Menghan Liu |
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| description | <b>Background/Objectives</b>: Diabetic kidney disease (DKD) is a common diabetic complication, driven by a multifactorial pathogenesis that includes various genetic components. However, the precise causative genes and their underlying biological pathways remain poorly understood. <b>Methods</b>: We performed a cross-tissue transcriptome-wide association study (TWAS) of DKD using expression quantitative trait loci (eQTL) data from 49 tissues in the Genotype—Tissue Expression (GTEx) version 8 (v8) resource. Five complementary analytical frameworks—sparse canonical correlation analysis (sCCA), functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), summary-data-based Mendelian randomization (SMR), and multi-marker analysis of genomic annotation (MAGMA)—were integrated to nominate candidate genes. Causal inference was refined using Mendelian randomization (MR), and biological significance was evaluated through pathway enrichment, protein interaction networks, and druggability profiling. <b>Results</b>: We identified 23 candidate genes associated with DKD risk, of which 13 were supported by MR analysis. Among these, 10 represent previously unreported susceptibility genes. Notably, four genes—<i>HLA-DRB1</i>, <i>HLA-DRB5</i>, <i>NOTCH4</i>, and <i>CYP21A2</i>—encode potentially druggable proteins, with <i>HLA-DRB5</i> and <i>CYP21A2</i> both qualifying as novel susceptibility genes and therapeutic targets. These genes converge on immune modulation, steroid biosynthesis, DNA repair, and transcriptional regulation—processes central to DKD pathogenesis. <b>Conclusions</b>: Our study represents the first systematic cross-tissue TWAS of DKD, revealing a prioritized set of genetically and functionally supported susceptibility genes. The identification of druggable targets among these genes provides critical insight into the mechanistic underpinnings of DKD and highlights their potential for future therapeutic development. These findings enhance our understanding of DKD pathophysiology and offer a foundation for precision medicine strategies in nephrology. |
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| institution | OA Journals |
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| language | English |
| publishDate | 2025-05-01 |
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| series | Biomedicines |
| spelling | doaj-art-ff59652d150e4be8b02e5601c7f432102025-08-20T02:33:38ZengMDPI AGBiomedicines2227-90592025-05-01135123110.3390/biomedicines13051231A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen CohortMenghan Liu0Zehua Li1Yao Lu2Pingping Sun3Ying Chen4Li Yang5Renal Division, Peking University Institute of Nephrology, Peking University First Hospital, Beijing 100034, ChinaRenal Division, Peking University Institute of Nephrology, Peking University First Hospital, Beijing 100034, ChinaRenal Division, Peking University Institute of Nephrology, Peking University First Hospital, Beijing 100034, ChinaDepartment of Internal Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100054, ChinaRenal Division, Peking University Institute of Nephrology, Peking University First Hospital, Beijing 100034, ChinaRenal Division, Peking University Institute of Nephrology, Peking University First Hospital, Beijing 100034, China<b>Background/Objectives</b>: Diabetic kidney disease (DKD) is a common diabetic complication, driven by a multifactorial pathogenesis that includes various genetic components. However, the precise causative genes and their underlying biological pathways remain poorly understood. <b>Methods</b>: We performed a cross-tissue transcriptome-wide association study (TWAS) of DKD using expression quantitative trait loci (eQTL) data from 49 tissues in the Genotype—Tissue Expression (GTEx) version 8 (v8) resource. Five complementary analytical frameworks—sparse canonical correlation analysis (sCCA), functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), summary-data-based Mendelian randomization (SMR), and multi-marker analysis of genomic annotation (MAGMA)—were integrated to nominate candidate genes. Causal inference was refined using Mendelian randomization (MR), and biological significance was evaluated through pathway enrichment, protein interaction networks, and druggability profiling. <b>Results</b>: We identified 23 candidate genes associated with DKD risk, of which 13 were supported by MR analysis. Among these, 10 represent previously unreported susceptibility genes. Notably, four genes—<i>HLA-DRB1</i>, <i>HLA-DRB5</i>, <i>NOTCH4</i>, and <i>CYP21A2</i>—encode potentially druggable proteins, with <i>HLA-DRB5</i> and <i>CYP21A2</i> both qualifying as novel susceptibility genes and therapeutic targets. These genes converge on immune modulation, steroid biosynthesis, DNA repair, and transcriptional regulation—processes central to DKD pathogenesis. <b>Conclusions</b>: Our study represents the first systematic cross-tissue TWAS of DKD, revealing a prioritized set of genetically and functionally supported susceptibility genes. The identification of druggable targets among these genes provides critical insight into the mechanistic underpinnings of DKD and highlights their potential for future therapeutic development. These findings enhance our understanding of DKD pathophysiology and offer a foundation for precision medicine strategies in nephrology.https://www.mdpi.com/2227-9059/13/5/1231diabetic kidney diseasecross-tissue transcriptome-wide association studynovel susceptibility genesdruggable targetMendelian randomization |
| spellingShingle | Menghan Liu Zehua Li Yao Lu Pingping Sun Ying Chen Li Yang A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen Cohort Biomedicines diabetic kidney disease cross-tissue transcriptome-wide association study novel susceptibility genes druggable target Mendelian randomization |
| title | A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen Cohort |
| title_full | A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen Cohort |
| title_fullStr | A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen Cohort |
| title_full_unstemmed | A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen Cohort |
| title_short | A Cross-Tissue Transcriptome-Wide Association Study Reveals Novel Susceptibility Genes for Diabetic Kidney Disease in the FinnGen Cohort |
| title_sort | cross tissue transcriptome wide association study reveals novel susceptibility genes for diabetic kidney disease in the finngen cohort |
| topic | diabetic kidney disease cross-tissue transcriptome-wide association study novel susceptibility genes druggable target Mendelian randomization |
| url | https://www.mdpi.com/2227-9059/13/5/1231 |
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