Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma
Isabelle Atkins
(1)
,
Ben Kinnersley
(1)
,
Quinn Ostrom
(2)
,
Karim Labreche
(1)
,
Dora Il'Yasova
(3, 4)
,
Georgina Armstrong
(2)
,
Jeanette Eckel-Passow
(5)
,
Minouk Schoemaker
(1)
,
Markus Nöthen
(6)
,
Jill Barnholtz-Sloan
(7)
,
Anthony Swerdlow
(1)
,
Matthias Simon
(8)
,
Preetha Rajaraman
(9)
,
Stephen Chanock
(9)
,
Joellen Shildkraut
(10)
,
Jonine Bernstein
(11)
,
Per Hoffmann
(12, 8)
,
Karl-Heinz Jöckel
(13)
,
Rose Lai
(14)
,
Elizabeth Claus
(15, 16)
,
Sara Olson
(17, 18)
,
Christoffer Johansen
(18, 17)
,
Margaret Wrensch
(19)
,
Beatrice Melin
(20)
,
Robert Jenkins
(5)
,
Marc Sanson
(21, 22)
,
Melissa Bondy
(2)
,
Richard Houlston
(1)
1
The institute of cancer research [London]
2 BCM - Baylor College of Medicine
3 Georgia State University
4 Duke University Medical Center
5 Mayo Clinic [Rochester]
6 Institute of Human Genetics [Erlangen, Allemagne]
7 Case Western Reserve University [Cleveland]
8 Universität Bonn = University of Bonn
9 NCI-NIH - National Cancer Institute [Bethesda]
10 University of Virginia
11 Memorial Sloane Kettering Cancer Center [New York]
12 Unibas - Université de Bâle = University of Basel = Basel Universität
13 Institute for Medical Informatics, Biometry and Epidemiology
14 Keck School of Medicine [Los Angeles]
15 YSPH - Yale School of Public Health
16 Brigham and Women's Hospital [Boston]
17 UCPH - University of Copenhagen = Københavns Universitet
18 Rigshospitalet [Copenhagen]
19 UC San Francisco - University of California [San Francisco]
20 Umeå University = Umeå Universitet
21 CHU Pitié-Salpêtrière [AP-HP]
22 ICM - Institut du Cerveau = Paris Brain Institute
2 BCM - Baylor College of Medicine
3 Georgia State University
4 Duke University Medical Center
5 Mayo Clinic [Rochester]
6 Institute of Human Genetics [Erlangen, Allemagne]
7 Case Western Reserve University [Cleveland]
8 Universität Bonn = University of Bonn
9 NCI-NIH - National Cancer Institute [Bethesda]
10 University of Virginia
11 Memorial Sloane Kettering Cancer Center [New York]
12 Unibas - Université de Bâle = University of Basel = Basel Universität
13 Institute for Medical Informatics, Biometry and Epidemiology
14 Keck School of Medicine [Los Angeles]
15 YSPH - Yale School of Public Health
16 Brigham and Women's Hospital [Boston]
17 UCPH - University of Copenhagen = Københavns Universitet
18 Rigshospitalet [Copenhagen]
19 UC San Francisco - University of California [San Francisco]
20 Umeå University = Umeå Universitet
21 CHU Pitié-Salpêtrière [AP-HP]
22 ICM - Institut du Cerveau = Paris Brain Institute
Quinn Ostrom
- Function : Author
- PersonId : 1256852
- ORCID : 0000-0003-3469-7558
Dora Il'Yasova
- Function : Author
- PersonId : 1377532
- ORCID : 0000-0003-4290-6794
Minouk Schoemaker
- Function : Author
- PersonId : 1377533
- ORCID : 0000-0001-8403-2234
Anthony Swerdlow
- Function : Author
- PersonId : 1377534
- ORCID : 0000-0001-5550-4159
Elizabeth Claus
- Function : Author
Richard Houlston
- Function : Author
- PersonId : 763713
- ORCID : 0000-0002-5268-0242
- IdRef : 229880568
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 noncoding 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 and 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. Significance: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.