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Cancer Res. 2019 Feb 1. pii: canres.2888.2018. doi: 10.1158/0008-5472.CAN-18-2888. [Epub ahead of print]

Transcriptome-wide association study identifies new candidate susceptibility genes for glioma.

Author information

1
Division of Genetics and Epidemiology, Institute of Cancer Research.
2
Division of Genetics and Epidemiology, Institute of Cancer Research Ben.Kinnersley@icr.ac.uk.
3
Dan L. Duncan Cancer Center, Baylor College of Medicine.
4
School of Public Health, Georgia State University.
5
Health Sciences Research, Mayo Clinic.
6
Institute of Human Genetics, University of Bonn.
7
General Medical Sciences-Oncology, Case Western Reserve University.
8
Neurosurgery, Evangelisches Klinikum Bethel.
9
National Cancer Institute.
10
Division of Cancer Epidemiology & Genetics, Occupational and Environmental Epidemiology Branch, National Cancer Institute, National Institutes of Health.
11
University of Virginia School of Medicine.
12
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center.
13
Department of Biomedicine, University of Basel.
14
Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen.
15
Preventive Medicine and Neurology, University of Southern California.
16
Department of Biostatistics, Yale University School of Public Health.
17
Oncology clinic, Rigshospitalet.
18
Department of Neurological Surgery, University of California, San Francisco.
19
Radiation Sciences, Umeå University.
20
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine.
21
Dept of Neurology, Hôpital de la Salpêtrière, Pierre & Marie Curie University.

Abstract

Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in non-coding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM, 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P<5.69×10-6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z=4.43, P=5.68×10-6). GALNT6 resides at least 55 Mb away from any previously-identified glioma risk variant, while all other 30 significantly-associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis.

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