A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD
Abstract Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder with environmental factors being the primary risk determinants. However, genetic factors also substantially contribute to the susceptibility and progression of COPD. Although genome-wide association studies (GW...
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Nature Portfolio
2024-11-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-80122-w |
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| author | Guanglei Chen Yaxian Jin Cancan Chu Yuhao Zheng Changfu Yang Yunzhi Chen Xing Zhu |
| author_facet | Guanglei Chen Yaxian Jin Cancan Chu Yuhao Zheng Changfu Yang Yunzhi Chen Xing Zhu |
| author_sort | Guanglei Chen |
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| description | Abstract Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder with environmental factors being the primary risk determinants. However, genetic factors also substantially contribute to the susceptibility and progression of COPD. Although genome-wide association studies (GWAS) have identified several loci associated with COPD susceptibility, the specific pathogenic genes underlying these loci, along with their biological functions and roles within regulatory networks, remain unclear. This lack of clarity constrains our ability to achieve a deeper understanding of the genetic basis of COPD. This study leveraged the FinnGen R11 genetic dataset, comprising 21,617 cases and 372,627 controls, along with GTEx V8 eQTLs data to conduct a cross-tissue transcriptome-wide association study (TWAS). Initially, we performed a cross-tissue TWAS analysis using the Unified Test for Molecular Signatures (UTMOST), followed by validation of the UTMOST findings in single tissues using the Functional Summary-based Imputation (FUSION) method and conditional and joint (COJO) analyses of the identified genes. Subsequently, candidate susceptibility genes were screened using Multi-marker Analysis of Genomic Annotation (MAGMA). The causal relationship between these candidate genes and COPD was further evaluated through summary data-based Mendelian randomization (SMR), colocalization analysis, and Mendelian randomization (MR). Additionally, the identified results were validated against the COPD dataset in the GWAS Catalog (GCST90399694). GeneMANIA was employed to further explore the functional significance of these susceptibility genes. In the cross-tissue TWAS analysis (UTMOST), we identified 17 susceptibility genes associated with COPD. Among these, a novel susceptibility gene, G protein-coupled receptor kinase 4 (GRK4), was validated through single-tissue TWAS (FUSION) and MAGMA analyses, with further confirmation via SMR, MR, and colocalization analyses. Moreover, GRK4 was validated in an independent dataset. This study identifies GRK4 as a potential novel susceptibility gene for COPD, which may influence disease risk by exacerbating inflammatory responses. The findings address gaps in previous single-tissue GWAS studies, revealing consistent expression and potential function of GRK4 across different tissues. However, considering the study’s limitations, further investigation and validation of GRK4’s role in COPD are warranted. |
| format | Article |
| id | doaj-art-df9c2074d0bd426bb024e2e3f4599429 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-df9c2074d0bd426bb024e2e3f45994292025-08-20T02:33:00ZengNature PortfolioScientific Reports2045-23222024-11-0114111710.1038/s41598-024-80122-wA cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPDGuanglei Chen0Yaxian Jin1Cancan Chu2Yuhao Zheng3Changfu Yang4Yunzhi Chen5Xing Zhu6Guizhou University of Traditional Chinese MedicineThe First Affiliated Hospital of Guizhou University of Traditional Chinese MedicineGuizhou University of Traditional Chinese MedicineGuizhou University of Traditional Chinese MedicineGuizhou University of Traditional Chinese MedicineGuizhou University of Traditional Chinese MedicineGuizhou University of Traditional Chinese MedicineAbstract Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder with environmental factors being the primary risk determinants. However, genetic factors also substantially contribute to the susceptibility and progression of COPD. Although genome-wide association studies (GWAS) have identified several loci associated with COPD susceptibility, the specific pathogenic genes underlying these loci, along with their biological functions and roles within regulatory networks, remain unclear. This lack of clarity constrains our ability to achieve a deeper understanding of the genetic basis of COPD. This study leveraged the FinnGen R11 genetic dataset, comprising 21,617 cases and 372,627 controls, along with GTEx V8 eQTLs data to conduct a cross-tissue transcriptome-wide association study (TWAS). Initially, we performed a cross-tissue TWAS analysis using the Unified Test for Molecular Signatures (UTMOST), followed by validation of the UTMOST findings in single tissues using the Functional Summary-based Imputation (FUSION) method and conditional and joint (COJO) analyses of the identified genes. Subsequently, candidate susceptibility genes were screened using Multi-marker Analysis of Genomic Annotation (MAGMA). The causal relationship between these candidate genes and COPD was further evaluated through summary data-based Mendelian randomization (SMR), colocalization analysis, and Mendelian randomization (MR). Additionally, the identified results were validated against the COPD dataset in the GWAS Catalog (GCST90399694). GeneMANIA was employed to further explore the functional significance of these susceptibility genes. In the cross-tissue TWAS analysis (UTMOST), we identified 17 susceptibility genes associated with COPD. Among these, a novel susceptibility gene, G protein-coupled receptor kinase 4 (GRK4), was validated through single-tissue TWAS (FUSION) and MAGMA analyses, with further confirmation via SMR, MR, and colocalization analyses. Moreover, GRK4 was validated in an independent dataset. This study identifies GRK4 as a potential novel susceptibility gene for COPD, which may influence disease risk by exacerbating inflammatory responses. The findings address gaps in previous single-tissue GWAS studies, revealing consistent expression and potential function of GRK4 across different tissues. However, considering the study’s limitations, further investigation and validation of GRK4’s role in COPD are warranted.https://doi.org/10.1038/s41598-024-80122-wCOPDCross-tissue TWASUTMOSTFUSIONMAGMACOJO |
| spellingShingle | Guanglei Chen Yaxian Jin Cancan Chu Yuhao Zheng Changfu Yang Yunzhi Chen Xing Zhu A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD Scientific Reports COPD Cross-tissue TWAS UTMOST FUSION MAGMA COJO |
| title | A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD |
| title_full | A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD |
| title_fullStr | A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD |
| title_full_unstemmed | A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD |
| title_short | A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD |
| title_sort | cross tissue transcriptome wide association study reveals grk4 as a novel susceptibility gene for copd |
| topic | COPD Cross-tissue TWAS UTMOST FUSION MAGMA COJO |
| url | https://doi.org/10.1038/s41598-024-80122-w |
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