Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Tang, Haibo, Wang, Jie, Deng, Peizhi, Li, Yalan, Cao, Yaoquan, Yi, Bo, Zhu, Liyong, Zhu, Shaihong, Lu, Yao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
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
_version_ 1785114156784943104
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
work_keys_str_mv AT tanghaibo transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT wangjie transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT dengpeizhi transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT liyalan transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT caoyaoquan transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT yibo transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT zhuliyong transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT zhushaihong transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes
AT luyao transcriptomewideassociationstudyderivedgenesaspotentialvisceraladiposetissuespecifictargetsfortype2diabetes