Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity

Abstract Anthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings...

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Autores principales:	Erika N. Scott, Galen E. B. Wright, Britt I. Drögemöller, Jafar S. Hasbullah, Erandika P. Gunaretnam, Fudan Miao, Amit P. Bhavsar, Fei Shen, Bryan P. Schneider, Bruce C. Carleton, Colin J. D. Ross
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/ef67d46dd6034a2687778555b536d940
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spelling	oai:doaj.org-article:ef67d46dd6034a2687778555b536d9402021-12-02T15:45:28ZTranscriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity10.1038/s41525-021-00199-42056-7944https://doaj.org/article/ef67d46dd6034a2687778555b536d9402021-05-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00199-4https://doaj.org/toc/2056-7944Abstract Anthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings requires further elucidation. We conducted a transcriptome-wide association study (TWAS) using our previous GWAS summary statistics (n = 280 patients) to identify gene expression-related associations with ACT. We identified a genetic association between decreased expression of GDF5 and ACT (Z-score = −4.30, P = 1.70 × 10−5), which was replicated in an independent cohort (n = 845 patients, P = 3.54 × 10−3). Additionally, cell viability of GDF5-silenced human cardiac myocytes was significantly decreased in response to anthracycline treatment. Subsequent gene set enrichment and pathway analyses of the TWAS data revealed that genes essential for survival, cardioprotection and response to anthracyclines, as well as genes involved in ribosomal, spliceosomal and cardiomyopathy pathways are important for the development of ACT.Erika N. ScottGalen E. B. WrightBritt I. DrögemöllerJafar S. HasbullahErandika P. GunaretnamFudan MiaoAmit P. BhavsarFei ShenBryan P. SchneiderBruce C. CarletonColin J. D. RossNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Erika N. Scott Galen E. B. Wright Britt I. Drögemöller Jafar S. Hasbullah Erandika P. Gunaretnam Fudan Miao Amit P. Bhavsar Fei Shen Bryan P. Schneider Bruce C. Carleton Colin J. D. Ross Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
description	Abstract Anthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings requires further elucidation. We conducted a transcriptome-wide association study (TWAS) using our previous GWAS summary statistics (n = 280 patients) to identify gene expression-related associations with ACT. We identified a genetic association between decreased expression of GDF5 and ACT (Z-score = −4.30, P = 1.70 × 10−5), which was replicated in an independent cohort (n = 845 patients, P = 3.54 × 10−3). Additionally, cell viability of GDF5-silenced human cardiac myocytes was significantly decreased in response to anthracycline treatment. Subsequent gene set enrichment and pathway analyses of the TWAS data revealed that genes essential for survival, cardioprotection and response to anthracyclines, as well as genes involved in ribosomal, spliceosomal and cardiomyopathy pathways are important for the development of ACT.
format	article
author	Erika N. Scott Galen E. B. Wright Britt I. Drögemöller Jafar S. Hasbullah Erandika P. Gunaretnam Fudan Miao Amit P. Bhavsar Fei Shen Bryan P. Schneider Bruce C. Carleton Colin J. D. Ross
author_facet	Erika N. Scott Galen E. B. Wright Britt I. Drögemöller Jafar S. Hasbullah Erandika P. Gunaretnam Fudan Miao Amit P. Bhavsar Fei Shen Bryan P. Schneider Bruce C. Carleton Colin J. D. Ross
author_sort	Erika N. Scott
title	Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
title_short	Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
title_full	Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
title_fullStr	Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
title_full_unstemmed	Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
title_sort	transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ef67d46dd6034a2687778555b536d940
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Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity

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