Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility

Abstract Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (e...

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Autores principales:	Jamie W. Robinson, Richard M. Martin, Spiridon Tsavachidis, Amy E. Howell, Caroline L. Relton, Georgina N. Armstrong, Melissa Bondy, Jie Zheng, Kathreena M. Kurian
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/671b6767142d465a88df9af27c9c410a
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spelling	oai:doaj.org-article:671b6767142d465a88df9af27c9c410a2021-12-02T10:48:21ZTranscriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility10.1038/s41598-021-82169-52045-2322https://doaj.org/article/671b6767142d465a88df9af27c9c410a2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82169-5https://doaj.org/toc/2045-2322Abstract Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.Jamie W. RobinsonRichard M. MartinSpiridon TsavachidisAmy E. HowellCaroline L. ReltonGeorgina N. ArmstrongMelissa BondyJie ZhengKathreena M. KurianNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jamie W. Robinson Richard M. Martin Spiridon Tsavachidis Amy E. Howell Caroline L. Relton Georgina N. Armstrong Melissa Bondy Jie Zheng Kathreena M. Kurian Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility
description	Abstract Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.
format	article
author	Jamie W. Robinson Richard M. Martin Spiridon Tsavachidis Amy E. Howell Caroline L. Relton Georgina N. Armstrong Melissa Bondy Jie Zheng Kathreena M. Kurian
author_facet	Jamie W. Robinson Richard M. Martin Spiridon Tsavachidis Amy E. Howell Caroline L. Relton Georgina N. Armstrong Melissa Bondy Jie Zheng Kathreena M. Kurian
author_sort	Jamie W. Robinson
title	Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility
title_short	Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility
title_full	Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility
title_fullStr	Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility
title_full_unstemmed	Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility
title_sort	transcriptome-wide mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/671b6767142d465a88df9af27c9c410a
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Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility

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