Genome-wide association study identifies five susceptibility loci for glioma

Shete, Sanjay; Hosking, Fay J.; Robertson, Lindsay; Dobbins, Sara E.; Sanson, Marc; Malmer, Beatrice; Simon, Matthias; Marie, Yannick; Boisselier, Blandine; Delattre, Jean Yves; Hoang-Xuân, Khê; Hallani, Soufiane El; Idbaïh, Ahmed; Zélénika, Diana; Andersson, Ulrika; Henriksson, Roger; Bergenheim, A. Tommy; Feychting, Maria; Lönn, Stefan; Ahlbom, Anders; Schramm, Johannes; Linnebank, Michael; Hemminki, Kari; Kumar, Rajiv; Hepworth, Sarah; Price, Amy; Armstrong, Georgina; Liu, Yanhong; Gu, Xiangjun; Yu, Robert; Lau, Ching C.; Schoemaker, Minouk J.; Muir, Kenneth; Swerdlow, Anthony; Lathrop, Mark; Bondy, Melissa L.; Houlston, Richard S.

doi:10.1038/ng.407

Cited by 709 publications

(669 citation statements)

References 35 publications

(42 reference statements)

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“…[17][18][19] Genetic variants located in genes involved in telomere maintenance, and in particular in hTERT (MIM 187270), the gene encoding the catalytic subunit of telomerase, have been associated with increased risk to cancer. [20][21][22][23][24][25][26][27] Among the better characterized cancer variants, the hTERT rs2075786 (c.2654 þ 269G/A) SNP has been associated with lung cancer risk. 28,29 However, no studies have reported any association between variants located at the hTERT locus and the risk of CRC.…”

Section: Introductionmentioning

confidence: 99%

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

et al. 2012

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Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative risk LScao45_AA ¼ 2.90; 95% confidence interval ¼ 1.02-8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.

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Section: Introductionmentioning

confidence: 99%

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

et al. 2012

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“…CDKN2B-AS1 resides in the 9p21 region that has been clearly associated with cardiovascular disease 17 , diabetes 18 , intracranial aneurysm 19 and glioma 20 . The antisense RNA encoded by CDKN2B-AS1 regulates neighbouring genes at 9p21, particularly CDKN2B with which its expression levels are reciprocally related 21 .…”

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confidence: 99%

“…This hypothesis is supported by observations that the opposite risk alleles in CDKN2B-AS1 are associated with glaucoma and glioma. For example, at rs4977756 and rs1063192, the G and C alleles respectively, are protective for glaucoma but are the risk alleles for glioma 20 . The direction of association is the same for glaucoma as for cardiovascular disease 17 and diabetes 18 , but further work is required to determine whether the same causative variant/s underlie these different disease associations.…”

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confidence: 99%

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

et al. 2011

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A genome-wide association study (GWAS) for open angle glaucoma (OAG) blindness was conducted using a discovery cohort of 590 cases with severe visual field loss and 3956 controls. Genome-wide significant associations were identified at TMCO1 (rs4656461 (G) OR=1.68, p=6.1x10 -10 ) and CDKN2B-AS1 (rs4977756 (A) OR = 1.50, p=4.7x10 -9 ). These findings were replicated in a second cohort of advanced OAG cases (rs4656461 p=0.010; rs4977756 p=0.042) and two further cohorts of less severe OAG. The study wide odds ratios are 1.51 (1.35-1.68), p=6.00x10 -14 at TMCO1, and 1.39 (1.28-1.51), p=1.35x10 -14 at CDKN2B-AS1 (also known as CDKN2BAS and ANRIL). Carriers of 1 or more risk alleles at both loci concurrently are at >3-fold increased risk of glaucoma. We demonstrate retinal expression of genes at both loci, and show that CDKN2A and CDKN2B are strongly upregulated in an animal model of glaucoma.Glaucoma is a group of neurodegenerative ocular diseases united by a clinically characteristic optic neuropathy. It is the second leading cause of blindness worldwide 1 . Primary open angle glaucoma (OAG) is the commonest subtype 1 . OAG pathogenesis and factors determining disease progression are poorly understood. Early intervention with measures to reduce intraocular pressure retards visual loss in most individuals 2 , but many cases of glaucoma remain undiagnosed until irreversible vision loss has occurred. Elucidation of SNPs associated with severe outcomes could enable better targeting of treatments which carry cost and morbidity, to individuals at highest risk of blindness. Linkage and candidate gene studies have identified several genes likely to be involved in OAG including myocilin 3 and NTF4 4 , although for the latter, findings have varied in different populations 5 . A recent GWAS using Icelandic OAG cases of unselected severity identified association with variants near CAV1 6 . To identify genes predisposing individuals to OAG blindness, we performed a GWAS in Australian Caucasians with advanced OAG (individuals with OAG who have progressed to severe visual field loss or blindness).

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“…SNPs in 9p21 locus were also found to be associated with various cancers, in addition to cardiovascular diseases and T2D. [81][82][83] So far, most of the GWAS did a fast-track replication by selecting the top few or top tens of SNPs with the most significant P-values in stage 1 and proceeding to replicate those SNPs in stage 2 or stage 3 with larger sample sizes. However, other SNPs down the significance list are just as likely to be genuine, thus more SNPs need to be selected for replication in larger sample sets.…”

Section: The Recent 2 Years: 2008 and 2009mentioning

confidence: 99%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

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It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

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Genome-wide association study identifies five susceptibility loci for glioma

Cited by 709 publications

References 35 publications

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

The pursuit of genome-wide association studies: where are we now?

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