Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis.
To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10(-49)); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations - BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10(-4) for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10(-3), for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10(-6)). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
Ben
http://orcid.org/0000-0003-1783-6296
B
Kinnersley
Foundation Jean Dausset-CEPH, Paris, France.
Yoichiro
http://orcid.org/0000-0001-8748-5597
Y
Kamatani
Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, Paris, France.
Marianne
M
Labussière
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
Yufei
Y
Wang
Université Paris 13 Sorbonne Paris Cité, Inserm (U557), Cnam, Bobigny, France.
Pilar
P
Galan
Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, Paris, France.|AP-HP, GH Pitié-Salpêtrière, Service de Neurologie Mazarin, Paris, France.
Karima
K
Mokhtari
Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, Paris, France.|AP-HP, GH Pitié-Salpêtrière, Service de Neurologie Mazarin, Paris, France.|Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Jean-Yves
JY
Delattre
Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
Konstantinos
K
Gousias
Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
Johannes
J
Schramm
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
Minouk J
MJ
Schoemaker
Division of Breast Cancer Research, The Institute of Cancer Research, Sutton, Surrey, UK.
Anthony
A
Swerdlow
Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Sarah J
SJ
Fleming
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Biomedicine, Division of Medical Genetics, University of Basel, Basel, Switzerland.
Stefan
S
Herms
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Stefanie
S
Heilmann
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Markus M
MM
Nöthen
Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
Matthias
M
Simon
Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, Paris, France.|AP-HP, GH Pitié-Salpêtrière, Service de Neurologie Mazarin, Paris, France.|Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Marc
M
Sanson
Foundation Jean Dausset-CEPH, Paris, France.|AP-HP, GH Pitié-Salpêtrière, Service de Neurologie Mazarin, Paris, France.|Department of Human Genetics, Génome Québec, McGill University, Montreal, QC, Canada.
Mark
M
Lathrop
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
Richard S
RS
Houlston
D000465:Algorithms; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D056426:Genetic Loci; D060005:Genotyping Techniques / Q000379:methods*; D005910:Glioma / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D000604:Amino Acyl-tRNA Synthetases; C093612:HARS2 protein, human