Dataset Information

Genome-wide association study of glioma and meta-analysis.

ABSTRACT: Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.

SUBMITTER: Rajaraman P

PROVIDER: S-EPMC3761216 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Genome-wide association study of glioma and meta-analysis.

Rajaraman Preetha P Melin Beatrice S BS Wang Zhaoming Z McKean-Cowdin Roberta R Michaud Dominique S DS Wang Sophia S SS Bondy Melissa M Houlston Richard R Jenkins Robert B RB Wrensch Margaret M Yeager Meredith M Ahlbom Anders A Albanes Demetrius D Andersson Ulrika U Freeman Laura E Beane LE Buring Julie E JE Butler Mary Ann MA Braganza Melissa M Carreon Tania T Feychting Maria M Fleming Sarah J SJ Gapstur Susan M SM Gaziano J Michael JM Giles Graham G GG Hallmans Goran G Henriksson Roger R Hoffman-Bolton Judith J Inskip Peter D PD Johansen Christoffer C Kitahara Cari M CM Lathrop Mark M Liu Chenwei C Le Marchand Loic L Linet Martha S MS Lonn Stefan S Peters Ulrike U Purdue Mark P MP Rothman Nathaniel N Ruder Avima M AM Sanson Marc M Sesso Howard D HD Severi Gianluca G Shu Xiao-Ou XO Simon Matthias M Stampfer Meir M Stevens Victoria L VL Visvanathan Kala K White Emily E Wolk Alicja A Zeleniuch-Jacquotte Anne A Zheng Wei W Decker Paul P Enciso-Mora Victor V Fridley Brooke B Gao Yu-Tang YT Kosel Matthew M Lachance Daniel H DH Lau Ching C Rice Terri T Swerdlow Anthony A Wiemels Joseph L JL Wiencke John K JK Shete Sanjay S Xiang Yong-Bing YB Xiao Yuanyuan Y Hoover Robert N RN Fraumeni Joseph F JF Chatterjee Nilanjan N Hartge Patricia P Chanock Stephen J SJ

Human genetics 20120811 12

Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, ...[more]

PMID: 22886559

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Project description:BackgroundGastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.ObjectiveGenetic predisposition may play a role; however, investigation at the genome-wide level has not been performed.MethodsWe carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene-set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls.ResultsWhile no SNP associations were detected at strict significance (p ≤ 5 × 10-8 ), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10-5 ), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10-7 ) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein-coding candidate genes. Gene-set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin-Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls).ConclusionWe report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory-motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.

Dataset Information

Genome-wide association study of glioma and meta-analysis.

Publications

Genome-wide association study of glioma and meta-analysis.

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