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Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes
AIMS/HYPOTHESIS: This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. METHODS: We examined the causal relationship between VAT and type 2 diabetes using bidirecti...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542736/ https://www.ncbi.nlm.nih.gov/pubmed/37540242 http://dx.doi.org/10.1007/s00125-023-05978-5 |
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author | Tang, Haibo Wang, Jie Deng, Peizhi Li, Yalan Cao, Yaoquan Yi, Bo Zhu, Liyong Zhu, Shaihong Lu, Yao |
author_facet | Tang, Haibo Wang, Jie Deng, Peizhi Li, Yalan Cao, Yaoquan Yi, Bo Zhu, Liyong Zhu, Shaihong Lu, Yao |
author_sort | Tang, Haibo |
collection | PubMed |
description | AIMS/HYPOTHESIS: This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. METHODS: We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. RESULTS: MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00125-023-05978-5) contains peer-reviewed but unedited supplementary material. |
format | Online Article Text |
id | pubmed-10542736 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-105427362023-10-03 Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes Tang, Haibo Wang, Jie Deng, Peizhi Li, Yalan Cao, Yaoquan Yi, Bo Zhu, Liyong Zhu, Shaihong Lu, Yao Diabetologia Article AIMS/HYPOTHESIS: This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. METHODS: We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. RESULTS: MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00125-023-05978-5) contains peer-reviewed but unedited supplementary material. Springer Berlin Heidelberg 2023-08-04 2023 /pmc/articles/PMC10542736/ /pubmed/37540242 http://dx.doi.org/10.1007/s00125-023-05978-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Tang, Haibo Wang, Jie Deng, Peizhi Li, Yalan Cao, Yaoquan Yi, Bo Zhu, Liyong Zhu, Shaihong Lu, Yao Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes |
title | Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes |
title_full | Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes |
title_fullStr | Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes |
title_full_unstemmed | Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes |
title_short | Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes |
title_sort | transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542736/ https://www.ncbi.nlm.nih.gov/pubmed/37540242 http://dx.doi.org/10.1007/s00125-023-05978-5 |
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