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Analysis of 60 Reported Glioma Risk SNP s Replicates Published GWAS Findings but Fails to Replicate Associations From Published Candidate‐Gene Studies
Author(s) -
Walsh Kyle M.,
Anderson Erik,
Hansen Helen M.,
Decker Paul A.,
Kosel Matt L.,
Kollmeyer Thomas,
Rice Terri,
Zheng Shichun,
Xiao Yuanyuan,
Chang Jeffrey S.,
McCoy Lucie S.,
Bracci Paige M.,
Wiemels Joe L.,
Pico Alexander R.,
Smirnov Ivan,
Lachance Daniel H.,
Sicotte Hugues,
EckelPassow Jeanette E.,
Wiencke John K.,
Jenkins Robert B.,
Wrensch Margaret R.
Publication year - 2013
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.21707
Subject(s) - genome wide association study , single nucleotide polymorphism , snp , cdkn2a , candidate gene , biology , genetics , genotyping , genetic association , glioma , snp genotyping , gene , genotype
Genomewide association studies ( GWAS ) and candidate‐gene studies have implicated single‐nucleotide polymorphisms ( SNP s) 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 SNP s selected from the literature (eight from GWAS and 52 from candidate‐gene studies) were successfully genotyped on an I llumina custom genotyping panel. Eight SNP s 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 SNP s 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 SNP s within these genes.