Dataset Information

Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.

ABSTRACT: To explore the impact of common variation on the risk of developing lung cancer, we conducted a two-phase genome-wide association (GWA) study. In phase 1, we compared the genotypes of 511,919 tagging single nucleotide polymorphisms (SNP) in 1,952 cases and 1,438 controls; in phase 2, 30,568 SNPs were genotyped in 2,465 cases and 3,005 controls. SNP selection was based on best supported P values from phase 1 and two other GWA studies of lung cancer. In the combined analysis of phases 1 and 2, the strongest associations identified were defined by SNPs mapping to 15q25.1 (rs12914385; P = 3.19 x 10(-16)), 5p15.33 (rs4975616; P = 6.66 x 10(-7)), and 6p21.33 (rs3117582; P = 9.13 x 10(-7)). Variation at 15q25.1, but not 5p15.33 or 6p21.33, was strongly associated with smoking behavior with risk alleles correlated to higher consumption. Variation at 5p15.33 was shown to significantly influence induction of lung cancer histology. Pooling data from the four series provided 21,620 genotypes for 7,560 cases and 8,205 controls. A meta-analysis provided increased support that variation at 15q25.1 (rs8034191; P = 3.24 x 10(-26)), 5p15.33 (rs4975616; P = 2.99 x 10(-9)), and 6p21.33 (rs3117582; P = 4.46 x 10(-10)) influences lung cancer risk. The next best-supported associations were attained at 15q15.2 (rs748404: P = 1.08 x 10(-6)) and 10q23.31 (rs1926203; P = 1.28 x 10(-6)). These data indicate few common variants account for 1% of the excess familial risk underscoring the necessity of having additional large sample series for gene discovery.

SUBMITTER: Broderick P

PROVIDER: S-EPMC2754318 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.

Broderick Peter P Wang Yufei Y Vijayakrishnan Jayaram J Matakidou Athena A Spitz Margaret R MR Eisen Timothy T Amos Christopher I CI Houlston Richard S RS

Cancer research 20090804 16

To explore the impact of common variation on the risk of developing lung cancer, we conducted a two-phase genome-wide association (GWA) study. In phase 1, we compared the genotypes of 511,919 tagging single nucleotide polymorphisms (SNP) in 1,952 cases and 1,438 controls; in phase 2, 30,568 SNPs were genotyped in 2,465 cases and 3,005 controls. SNP selection was based on best supported P values from phase 1 and two other GWA studies of lung cancer. In the combined analysis of phases 1 and 2, the ...[more]

PMID: 19654303

Similar Datasets

Project description:BackgroundBipolar disorder is a highly heritable neuropsychiatric condition affecting more than 1% of the human population. Lithium salts are commonly prescribed as a mood stabilizer for individuals with bipolar disorder. Lithium is clinically effective in approximately half of treated individuals, and their genetic backgrounds are known to influence treatment outcomes. While the mechanism of lithium's therapeutic action is unclear, it stimulates adult neural progenitor cell proliferation, similar to some antidepressant drugs.MethodsTo identify common genetic variants that modulate lithium-induced proliferation, we conducted an EdU incorporation assay in a library of 80 genotyped human neural progenitor cells treated with lithium. These data were used to perform a genome-wide association study to identify common genetic variants that influence lithium-induced neural progenitor cell proliferation. We manipulated the expression of a putatively causal gene using CRISPRi/a (clustered regularly interspaced short palindromic repeats interference/activation) constructs to experimentally verify lithium-induced proliferation effects.ResultsWe identified a locus on chr3p21.1 associated with lithium-induced proliferation. This locus is also associated with bipolar disorder risk, schizophrenia risk, and interindividual differences in intelligence. We identified a single gene, GNL3, whose expression temporally increased in an allele-specific fashion following lithium treatment. Experimentally increasing the expression of GNL3 led to increased proliferation under baseline conditions, while experimentally decreasing GNL3 expression suppressed lithium-induced proliferation.ConclusionsOur experiments reveal that common genetic variation modulates lithium-induced neural progenitor proliferation and that GNL3 expression is necessary for the full proliferation-stimulating effects of lithium. These results suggest that performing genome-wide associations in genetically diverse human cell lines is a useful approach to discover context-specific pharmacogenomic effects.

Project description:Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs).Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n?=?15,748; controls, n?=?18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n?=?14,160; controls, n?=?12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n?=?12,160; controls, n?=?16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma.We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value?=?1.9?×?10-6; top gene RORA, gene P value?=?0.0003), prostate (pathway P value?=?4.1?×?10-6; top gene ARNTL, gene P value?=?0.0002) and lung cancer (pathway P value?=?6.9?×?10-7; top gene RORA, gene P value?=?2.0?×?10-6), as well as all their subgroups. Out of 17 genes investigated, 15 were found to be significantly associated with the risk of cancer: four genes were shared by all three malignancies (ARNTL, CLOCK, RORA and RORB), two by breast and lung cancer (CRY1 and CRY2) and three by prostate and lung cancer (NPAS2, NR1D1 and PER3), whereas four genes were specific for lung cancer (ARNTL2, CSNK1E, NR1D2 and PER2) and two for breast cancer (PER1, RORC).Our findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition.

Project description:BackgroundThoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse.ResultsFracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb - 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p < 0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 × 10(-4)), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042).ConclusionsFracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses.

Project description:ImportanceThe familial aspect of acute appendicitis (AA) has been proposed, but its hereditary basis remains undetermined.ObjectiveTo identify genomic variants associated with AA.Design, setting, and participantsThis genome-wide association study, conducted from June 21, 2019, to February 4, 2020, used a multi-institutional biobank to retrospectively identify patients with AA across 8 single-nucleotide variation (SNV) genotyping batches. The study also examined differential gene expression in appendiceal tissue samples between patients with AA and controls using the GSE9579 data set in the National Institutes of Health's Gene Expression Omnibus repository. Statistical analysis was conducted from October 1, 2019, to February 4, 2020.Main outcomes and measuresSingle-nucleotide variations with a minor allele frequency of 5% or higher were tested for association with AA using a linear mixed model. The significance threshold was set at P = 5 × 10-8.ResultsA total of 29 706 patients (15 088 women [50.8%]; mean [SD] age at enrollment, 60.1 [17.0] years) were included, 1743 of whom had a history of AA. The genomic inflation factor for the cohort was 1.003. A previously unknown SNV at chromosome 18q was found to be associated with AA (rs9953918: odds ratio, 0.99; 95% CI, 0.98-1.00; P = 4.48 × 10-8). This SNV is located in an intron of the NEDD4L gene. The heritability of appendicitis was estimated at 30.1%. Gene expression data from appendiceal tissue donors identified NEDD4L to be among the most differentially expressed genes (14 of 22 216 genes; β [SE] = -2.71 [0.44]; log fold change = -1.69; adjusted P = .04).Conclusions and relevanceThis study identified SNVs within the NEDD4L gene as being associated with AA. Nedd4l is involved in the ubiquitination of intestinal ion channels and decreased Nedd4l activity may be implicated in the pathogenesis of AA. These findings can improve the understanding of the genetic predisposition to and pathogenesis of AA.

Dataset Information

Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.

Publications

Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets