title: Analysis of 60 reported glioma risk SNPs replicates published GWAS findings but fails to replicate associations from published candidate-gene studies.
abstract: Genomewide association studies (GWAS) and candidate-gene studies have implicated single-nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case-control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate-gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate-gene studies was associated in the full case-control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate-gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. Kyle.Walsh@ucsf.edu
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.forename: Erik
authors.initials: E
authors.lastname: Anderson
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.forename: Paul A
authors.initials: PA
authors.lastname: Decker
authors.forename: Matt L
authors.initials: ML
authors.lastname: Kosel
authors.forename: Thomas
authors.initials: T
authors.lastname: Kollmeyer
authors.forename: Terri
authors.initials: T
authors.lastname: Rice
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Chang
authors.forename: Lucie S
authors.initials: LS
authors.lastname: McCoy
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: Joe L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Pico
authors.forename: Ivan
authors.initials: I
authors.lastname: Smirnov
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Lachance
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
mesh_terms: D000368:Aged; D002140:California; D016022:Case-Control Studies; D016543:Central Nervous System Neoplasms / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D019942:Genes, p16; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005910:Glioma / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding; D019098:Telomerase / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C487973:PHLDB1 protein, human; D062085:RNA, Long Noncoding; C000613877:long noncoding RNA CCDC26, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C509186:TERT protein, human; D019098:Telomerase; C532890:RTEL1 protein, human; D004265:DNA Helicases