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.

Genome-Wide Association Studies in Glioma

“…27). A number of additional studies have replicated the association between rs78378222 and glioma risk (20, 32, 113, 114). …”

“…Indeed, a recent study of 1,662 cases and 1,301 controls failed to replicate 52 variants previously implicated by candidate gene studies (20). In combination with more systematic approaches such as those making use of the exome array (21), these studies do not currently provide support for this class of susceptibility allele playing a major role in glioma predisposition.…”

The RTEL1 rs6010620 Polymorphism and Glioma Risk: a Meta-analysis Based on 12 Case-control Studies

“…The gene polymorphisms increased or decreased glioma sensibility by regulating the proliferation and apoptosis of cells (Das et al, 2013;Liang et al, 2013). (Das et al, 2013;Li et al, 2013b) (Shete et al, 2009;Wrensch et al, 2009;Jin et al, 2013;Li et al, 2013;Walcott et al, 2013;Walsh et al, 2013a;Walsh et al, 2013b). Several research groups have reported associations between the rs6010620 single nucleotide polymorphism (SNP) and glioma risk.…”

Polymorphisms in IL-4/IL-13 pathway genes and glioma risk: an updated meta-analysis

“…Additionally, the published meta-analyses were based on the testing of multiple models (homozygote comparison, heterozygote comparison, recessive model, and dominant model), which are not independent so may increase the risk of false-positive results. Furthermore, some studies were not included in previous meta-analyses [20,21], including those published later with larger sample sizes and rigorous designs [22,23]. Considering that these factors could contribute to bias in the final results, we carried out an updated metaanalysis to provide a more reliable correlation between polymorphisms in IL-4/IL-13 pathway genes and glioma risk.…”