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

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Downloads (Pure)

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=1,194 and whole blood, n=31,684) and glioma subtype (all glioma (7,400 cases, 8,257 controls) glioblastoma (GBM, 3,112 cases) and non-GBM gliomas (2,411 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.
Original languageEnglish
Article number2329
Number of pages10
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 27 Jan 2021

Bibliographical note

Funding Information:
This work was supported by the Medical Research Council (MRC)/University of Bristol Integrative Epidemiology Unit (IEU) and is supported by the MRC and the University of Bristol (MC_UU_12013/1, MC_UU_12013/2). JWR is supported by a joint studentship from NHS North Bristol Trust, Southmead Hospital Charity and Bristol Brain Tumour Bank (SOCS/SJ1447). JZ is funded by the Vice-Chancellor’s fellowship. CLR and RMM is supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/ A29019). JWR, RMM, AEH, CLR and JZ are members of the MRC IEU which is supported by the Medical Research Council and the University of Bristol (MC_UU_12013/1-9). RMM is supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre which is funded by the National Institute for Health Research and is a partnership between University Hospitals Bristol NHS Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. The funders took no active role in the production of this research.

Publisher Copyright:
© 2021, The Author(s).

Structured keywords

  • ICEP

Fingerprint

Dive into the research topics of 'Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility'. Together they form a unique fingerprint.

Cite this