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Sökning: WFRF:(Obeidat Ma'en)

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1.
  • Artigas Soler, María, et al. (författare)
  • Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
  • 2011
  • Ingår i: Nature genetics. - 1546-1718. ; 43:11, s. 1082-90
  • Tidskriftsartikel (refereegranskat)abstract
    • Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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2.
  • Bossé, Yohan, et al. (författare)
  • Transcriptome-wide association study reveals candidate causal genes for lung cancer
  • 2020
  • Ingår i: International Journal of Cancer. - John Wiley and Sons Inc.. - 0020-7136. ; 146:7, s. 1862-1878
  • Tidskriftsartikel (refereegranskat)abstract
    • We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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3.
  • Fehringer, Gordon, et al. (författare)
  • Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations
  • 2016
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:17, s. 5103-5114
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.</p>
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4.
  • Hancock, Dana B, et al. (författare)
  • Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
  • 2012
  • Ingår i: PLoS genetics. - 1553-7404. ; 8:12, s. e1003098
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV<sub>1</sub>), and its ratio to forced vital capacity (FEV<sub>1</sub>/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV<sub>1</sub> and FEV<sub>1</sub>/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near <em>DNER</em> (smallest <em>P</em><sub>JMA = </sub>5.00×10<sup>−11</sup>), <em>HLA-DQB1</em> and <em>HLA-DQA2</em> (smallest <em>P</em><sub>JMA = </sub>4.35×10<sup>−9</sup>), and <em>KCNJ2</em> and <em>SOX9</em> (smallest <em>P</em><sub>JMA = </sub>1.28×10<sup>−8</sup>) were associated with FEV<sub>1</sub>/FVC or FEV<sub>1</sub> in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated <em>DNER</em>, <em>KCNJ2</em>, and <em>SOX9</em> and found them to be expressed in human lung tissue. <em>DNER</em> and <em>SOX9</em> further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.</p>
5.
  • Jackson, Victoria E, et al. (författare)
  • Meta-analysis of exome array data identifies six novel genetic loci for lung function.
  • 2018
  • Ingår i: Wellcome open research. - 2398-502X. ; 3
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Background:</strong> Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. <strong>Methods:</strong> We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV <sub>1</sub>), forced vital capacity (FVC) and the ratio of FEV <sub>1</sub> to FVC (FEV <sub>1</sub>/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. <strong>Results:</strong> We identified significant (P&lt;2·8x10 <sup>-7</sup>) associations with six SNPs: a nonsynonymous variant in <em>RPAP1</em>, which is predicted to be damaging, three intronic SNPs ( <em>SEC24C, CASC17</em> and <em>UQCC1</em>) and two intergenic SNPs near to <em>LY86</em> and <em>FGF10.</em> Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including <em>TYRO3</em> and <em>PLAU</em>. <strong>Conclusions:</strong> Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.</p>
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6.
  • Ji, Xuemei, et al. (författare)
  • Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
  • 2018
  • Ingår i: Nature Communications. - NATURE PUBLISHING GROUP. - 2041-1723 .- 2041-1723. ; 9, s. 1-15
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.</p>
7.
  • McKay, James D., et al. (författare)
  • Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
  • 2017
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.</p>
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8.
  • Obeidat, Ma'en, et al. (författare)
  • A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample
  • 2011
  • Ingår i: PLoS ONE. - 1932-6203 .- 1932-6203. ; 6:5, s. e19382
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Rationale: </strong></p> <p>Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).</p> <p><strong>Objectives:</strong></p> <p>To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.</p> <p><strong>Methods:</strong></p> <p>We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations.</p> <p><strong>Results:</strong></p> <p>The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3 x 10(-5). The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81 x 10(-5)), CNTN5 (P = 4.37 x 10(-4)), and TRPV4 (P = 1.58 x 10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41 x 10(-5)), followed by PDE4D (P = 1.22 x 10(-4)). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38 x 10(-4)), and ESR1 (P = 5.42 x 10(-4)) among ever-smokers.</p> <p><strong>Conclusions: </strong></p> <p>Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.</p>
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9.
  • Repapi, Emmanouela, et al. (författare)
  • Genome-wide association study identifies five loci associated with lung function.
  • 2010
  • Ingår i: Nature genetics. - 1546-1718. ; 42:1, s. 36-44
  • Tidskriftsartikel (refereegranskat)abstract
    • Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
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10.
  • Repapi, Emmanouela, et al. (författare)
  • Genome-wide association study identifies five loci associated with lung function
  • 2010
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 42:1, s. 36-44
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV<sub>1</sub>) and the ratio of FEV<sub>1</sub> to forced vital capacity (FVC) in the SpiroMeta consortium (<em>n</em> = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (<em>n</em> ≤ 32,184 additional individuals) and <em>in silico</em> summary association data from the CHARGE Consortium (<em>n</em> = 21,209) and the Health 2000 survey (<em>n</em> ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV<sub>1</sub> or FEV<sub>1</sub>/FVC and common variants at five additional loci: 2q35 in <em>TNS1</em> (<em>P</em> = 1.11 × 10<sup>−12</sup>), 4q24 in <em>GSTCD</em> (2.18 × 10<sup>−23</sup>), 5q33 in <em>HTR4</em> (<em>P</em> = 4.29 × 10<sup>−9</sup>), 6p21 in <em>AGER</em> (<em>P</em> = 3.07 × 10<sup>−15</sup>) and 15q23 in <em>THSD4</em> (<em>P</em> = 7.24 × 10<sup>−15</sup>). mRNA analyses showed expression of <em>TNS1</em>, <em>GSTCD</em>, <em>AGER</em>, <em>HTR4</em> and <em>THSD4</em> in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.</p>
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