PLoS Articles

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UNC-authored articles published by the Public Library of Science (PLoS)

Works (1963)

1911. A genetic switch controls the production of flagella and toxins in Clostridium difficile

Title Tesim:: A genetic switch controls the production of flagella and toxins in Clostridium difficile
Creator:: Anjuwon-Foster, Brandon R. and Tamayo, Rita
Date of publication:: 2017
Abstract Tesim:: In the human intestinal pathogen Clostridium difficile, flagella promote adherence to intestinal epithelial cells. Flagellar gene expression also indirectly impacts production of the glucosylating toxins, which are essential to diarrheal disease development. Thus, factors that regulate the expression of the flgB operon will likely impact toxin production in addition to flagellar motility. Here, we report the identification a “flagellar switch” that controls the phase variable production of flagella and glucosylating toxins. The flagellar switch, located upstream of the flgB operon containing the early stage flagellar genes, is a 154 bp invertible sequence flanked by 21 bp inverted repeats. Bacteria with the sequence in one orientation expressed flagellum and toxin genes, produced flagella, and secreted the toxins (“flg phase ON”). Bacteria with the sequence in the inverse orientation were attenuated for flagellar and toxin gene expression, were aflagellate, and showed decreased toxin secretion (“flg phase OFF”). The orientation of the flagellar switch is reversible during growth in vitro. We provide evidence that gene regulation via the flagellar switch occurs post-transcription initiation and requires a C. difficile-specific regulatory factor to destabilize or degrade the early flagellar gene mRNA when the flagellar switch is in the OFF orientation. Lastly, through mutagenesis and characterization of flagellar phase locked isolates, we determined that the tyrosine recombinase RecV, which catalyzes inversion at the cwpV switch, is also responsible for inversion at the flagellar switch in both directions. Phase variable flagellar motility and toxin production suggests that these important virulence factors have both advantageous and detrimental effects during the course of infection.
Resource type:: Article
Affiliation Label Tesim:: Department of Microbiology and Immunology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/2mrm-a241
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006701, PMCID: PMC5386303, PMID: 28346491, and Onescience id: f31743d6d4eb1003aa7adc6d1254556524dde993
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 3
Journal Title:: PLoS Genetics
Journal Volume:: 13
Keyword:: Base Sequence, Blotting, Western, Blotting, Northern, Flagella, Intestines, Gene Expression Regulation, Bacterial, Movement, Bacterial Toxins, Operon, Humans, Microscopy, Fluorescence, Clostridium difficile, Bacterial Proteins, and Enterocolitis, Pseudomembranous
Language Label:: English
ORCID:: 0000-0002-1140-4321 and 0000-0002-3745-3316
Page Start:: e1006701
Person:: Anjuwon-Foster, Brandon R. and Tamayo, Rita
Rights Statement Label:: In Copyright
Source:: sb397f326

1912. The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1

Title Tesim:: The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1
Creator:: Nigrovic, Peter A., Plenge, Robert M., Cunin, Pierre, Yang, Yu, Wu, Di, Okada, Yukinori, Diogo, Dorothée, and Li, Gang
Date of publication:: 2016
Abstract Tesim:: Understanding the implications of genome-wide association studies (GWAS) for disease biology requires both identification of causal variants and definition of how these variants alter gene function. The non-coding triallelic dinucleotide polymorphism CCR6DNP is associated with risk for rheumatoid arthritis, and is considered likely causal because allelic variation correlates with expression of the chemokine receptor CCR6. Using transcription activator-like effector nuclease (TALEN) gene editing, we confirmed that CCR6DNP regulates CCR6. To identify the associated transcription factor, we applied a novel assay, Flanking Restriction Enhanced Pulldown (FREP), to identify specific association of poly (ADP-ribose) polymerase 1 (PARP-1) with CCR6DNP consistent with the established allelic risk hierarchy. Correspondingly, manipulation of PARP-1 expression or activity impaired CCR6 expression in several lineages. These findings show that CCR6DNP is a causal variant through which PARP-1 regulates CCR6, and introduce a highly efficient approach to interrogate non-coding genetic polymorphisms associated with human disease.
Resource type:: Article
Affiliation Label Tesim:: Department of Periodontology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/bzcj-sm19
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006292, PMCID: PMC5023119, Onescience id: d292336ace43c3f7c7cbcb094fb9a9fa905035ca, and PMID: 27626929
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 9
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: Genetic Loci, Bioengineering, Genetics, Synthetic bioengineering, White Blood Cells, Proteins, Medicine and Health Sciences, Cell Biology, Gene Regulation, Gene Expression, Animal Cells, T Cells, Molecular Biology Techniques, Genome engineering, Immune Cells, Molecular Biology, Immunology, Blood Cells, Biology and Life Sciences, Cloning, Biology and life sciences, DNA-binding proteins, Cellular Types, Biochemistry, and Biotechnology
Language Label:: English
ORCID:
Other Affiliation:: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital, Division of Immunology; Boston Children’s Hospital, Merck Research Laboratories, Centre for Cancer Research; Monash Institute of Medical Research; Monash University, Department of Statistics; Harvard University, Department of Statistical Genetics; Osaka University Graduate School of Medicine, Department of Human Genetics and Disease Diversity; Graduate School of Medical and Dental Sciences; Tokyo Medical and Dental University, Laboratory for Statistical Analysis; RIKEN Center for Integrative Medical Sciences, Program in Medical and Population Genetics; Broad Institute, and Division of Genetics; Brigham and Women's Hospital; Harvard Medical School
Page Start:: e1006292
Person:: Nigrovic, Peter A., Plenge, Robert M., Cunin, Pierre, Yang, Yu, Wu, Di, Okada, Yukinori, Diogo, Dorothée, and Li, Gang
Rights Statement Label:: In Copyright
Source:: gf06g8008

1913. The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts

Title Tesim:: The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts
Creator:: Mieczkowski, Piotr A., Malc, Ewa P., Roberts, Steven A., Fargo, David C., Kaufmann, William K., Dai, Shuangshuang, Cortes-Ciriano, Isidro, Taylor, Jack A., Park, Peter J., Lee, Eunjung, Saini, Natalie, Grimm, Sara A., Chan, Kin, Klimczak, Leszek J., Boyer, Jayne C., Gordenin, Dmitry A., and Schurman, Shepherd H.
Date of publication:: 2016
Abstract Tesim:: Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging and cancer. Understanding the impacts of these processes on mutagenesis is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases. Previous methods relying on either the generation of induced pluripotent stem cells, or sequencing of single-cell genomes were inherently error-prone and did not allow independent validation of the mutations. In the current study we eliminated these potential sources of error by high coverage genome sequencing of single-cell derived clonal fibroblast lineages, obtained after minimal propagation in culture, prepared from skin biopsies of two healthy adult humans. We report here accurate measurement of genome-wide magnitude and spectra of mutations accrued in skin fibroblasts of healthy adult humans. We found that every cell contains at least one chromosomal rearrangement and 600–13,000 base substitutions. The spectra and correlation of base substitutions with epigenomic features resemble many cancers. Moreover, because biopsies were taken from body parts differing by sun exposure, we can delineate the precise contributions of environmental and endogenous factors to the accrual of genetic changes within the same individual. We show here that UV-induced and endogenous DNA damage can have a comparable impact on the somatic mutation loads in skin fibroblasts.
Resource type:: Article
Affiliation Label Tesim:: Department of Genetics, Department of Pathology and Laboratory Medicine, and Department of Environmental Sciences and Engineering
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/0byj-a360
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006385, PMID: 27788131, PMCID: PMC5082821, and Onescience id: 6bdc321877f4ca8387b0c67a10382fe2bb458807
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 10
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: Limbs (Anatomy), Fibroblasts, Cell Biology, Connective Tissue Cells, Biological Tissue, Musculoskeletal System, Biopsy, Animal Cells, Mutation, Cloning, Genetics, Anatomy, Gene Identification and Analysis, Connective Tissue, Medicine and Health Sciences, Surgical and Invasive Medical Procedures, Cellular Types, Biology and Life Sciences, Mutation Detection, Molecular Biology Techniques, Arms, Forearms, Molecular Biology, Somatic Mutation, and Oncology
Language Label:: English
ORCID:: , 0000-0002-3628-5808, 0000-0003-3048-2576, 0000-0001-5132-5428, and 0000-0002-8399-1836
Other Affiliation:: School of Molecular Biosciences; Washington State University, Integrative Bioinformatics Support Group; National Institute of Environmental Health Sciences; US National Institutes of Health, Department of Biomedical Informatics; Harvard Medical School, Epidemiology Branch; National Institute of Environmental Health Sciences; US National Institutes of Health, Division of Genetics; Brigham and Women’s Hospital, Genome Integrity and Structural Biology Laboratory; National Institute of Environmental Health Sciences; US National Institutes of Health, and Clinical Research Unit; National Institute of Environmental Health Sciences; US National Institutes of Health
Page Start:: e1006385
Person:: Mieczkowski, Piotr A., Malc, Ewa P., Roberts, Steven A., Fargo, David C., Kaufmann, William K., Dai, Shuangshuang, Cortes-Ciriano, Isidro, Taylor, Jack A., Park, Peter J., Lee, Eunjung, Saini, Natalie, Grimm, Sara A., Chan, Kin, Klimczak, Leszek J., Boyer, Jayne C., Gordenin, Dmitry A., and Schurman, Shepherd H.
Rights Statement Label:: In Copyright
Source:: 79408327p

1914. Recombination Rate Heterogeneity within Arabidopsis Disease Resistance Genes

Title Tesim:: Recombination Rate Heterogeneity within Arabidopsis Disease Resistance Genes
Creator:: Hardcastle, Thomas J., Choi, Kyuha, Jackson, Matthew, Ziolkowski, Piotr A., Griffin, Catherine, Reinhard, Carsten, McVean, Gil, Zhao, Xiaohui, Underwood, Charles J., Copenhaver, Gregory P., Yelina, Nataliya E., Henderson, Ian R., Serra, Heïdi, and Mézard, Christine
Date of publication:: 2016
Abstract Tesim:: Meiotic crossover frequency varies extensively along chromosomes and is typically concentrated in hotspots. As recombination increases genetic diversity, hotspots are predicted to occur at immunity genes, where variation may be beneficial. A major component of plant immunity is recognition of pathogen Avirulence (Avr) effectors by resistance (R) genes that encode NBS-LRR domain proteins. Therefore, we sought to test whether NBS-LRR genes would overlap with meiotic crossover hotspots using experimental genetics in Arabidopsis thaliana. NBS-LRR genes tend to physically cluster in plant genomes; for example, in Arabidopsis most are located in large clusters on the south arms of chromosomes 1 and 5. We experimentally mapped 1,439 crossovers within these clusters and observed NBS-LRR gene associated hotspots, which were also detected as historical hotspots via analysis of linkage disequilibrium. However, we also observed NBS-LRR gene coldspots, which in some cases correlate with structural heterozygosity. To study recombination at the fine-scale we used high-throughput sequencing to analyze ~1,000 crossovers within the RESISTANCE TO ALBUGO CANDIDA1 (RAC1) R gene hotspot. This revealed elevated intragenic crossovers, overlapping nucleosome-occupied exons that encode the TIR, NBS and LRR domains. The highest RAC1 recombination frequency was promoter-proximal and overlapped CTT-repeat DNA sequence motifs, which have previously been associated with plant crossover hotspots. Additionally, we show a significant influence of natural genetic variation on NBS-LRR cluster recombination rates, using crosses between Arabidopsis ecotypes. In conclusion, we show that a subset of NBS-LRR genes are strong hotspots, whereas others are coldspots. This reveals a complex recombination landscape in Arabidopsis NBS-LRR genes, which we propose results from varying coevolutionary pressures exerted by host-pathogen relationships, and is influenced by structural heterozygosity.
Resource type:: Article
Affiliation Label Tesim:: Integrative Program for Biological and Genome Sciences
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/6r18-vv55
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006179, PMCID: PMC4945094, PMID: 27415776, and Onescience id: e1294c747a482f15418a11b77455ea66b0a3b3e1
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 7
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: Arabidopsis, Arabidopsis Proteins, Plant Diseases, Heterozygote, Recombination, Genetic, Disease Resistance, Multigene Family, Crosses, Genetic, Nucleic Acid Hybridization, Genes, Plant, Meiosis, Linkage Disequilibrium, Pollen, Alleles, Genetic Variation, and RAC1 protein, Arabidopsis
Language Label:: English
ORCID:: 0000-0002-9328-5011, , 0000-0001-8862-1386, 0000-0001-9922-2815, 0000-0001-5730-6279, and 0000-0002-7962-3862
Other Affiliation:: Department of Plant Sciences; University of Cambridge, Department of Biotechnology; Adam Mickiewicz University, The Wellcome Trust Centre for Human Genetics; University of Oxford, Watson School of Biological Sciences; Cold Spring Harbor Laboratory; Cold Spring Harbor, School of Medicine, and Institut Jean-Pierre Bourgin; INRA; AgroParisTech; CNRS; Université Paris-Saclay; RD10
Page Start:: e1006179
Person:: Hardcastle, Thomas J., Choi, Kyuha, Jackson, Matthew, Ziolkowski, Piotr A., Griffin, Catherine, Reinhard, Carsten, McVean, Gil, Zhao, Xiaohui, Underwood, Charles J., Copenhaver, Gregory P., Yelina, Nataliya E., Henderson, Ian R., Serra, Heïdi, and Mézard, Christine
Rights Statement Label:: In Copyright
Source:: m613n3526

1915. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Title Tesim:: Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
Creator:: Hart, Deborah J., Rivadeneira, Fernando, Lane, Nancy E., Muir, Kenneth, Evangelou, Evangelos, Doherty, Sally, Castaño-Betancourt, Martha C., Meulenbelt, Ingrid, Boer, Cindy G., Styrkarsdottir, Unnur, Uitterlinden, Andre G., Doherty, Michael, Maciewicz, Rose A., Metrustry, Sarah, Evans, Dan S., den Hollander, Wouter, Barrett-Connor, Elizabeth, Jordan, Joanne M., Kloppenburg, Margreet, van Meurs, Joyce B. J., Lafeber, Floris, Slagboom, Eline P., Nelissen, Rob G. H. H., Yau, Michelle S., Mitchell, Braxton D., Nevitt, Michael C., Ramos, Yolande F. M., Liu, Youfang, Kraaij, Robert, Hofman, Albert, Valdes, Ana M., van Rooij, Jeroen, Kraus, Virginia B., Arden, Nigel, Zeggini, Eleftheria, Zhang, Weiya, and Spector, Tim D.
Date of publication:: 2016
Abstract Tesim:: Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
Resource type:: Article
Affiliation Label Tesim:: Thurston Arthritis Research Center
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/ayp9-a134
Identifier:: Onescience id: 30a2c4e0d724b1238defbacf6a6a919b42275a48, PMCID: PMC5049763, PMID: 27701424, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1006260
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 10
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: Hip, Genome Analysis, Joints (Anatomy), Cartilage, Cancer Research, Genetic Loci, 0604 Genetics, Molecular Biology, Genetics(clinical), Computational Biology, Biology and Life Sciences, Anatomy, Rheumatology, Research Article, Pelvis, Arthritis, Phenotypes, Genome-Wide Association Studies, QH426-470, Gene Expression, Medicine and Health Sciences, Genetics, Human Genetics, Genomics, and Ecology, Evolution, Behavior and Systematics
Language Label:: English
ORCID:: , 0000-0003-4809-0044, and 0000-0001-9754-073X
Other Affiliation:: Department of Twins Research and Genetic Epidemiology Unit; King’s College London, Department of Internal Medicine; Erasmus Medical Center, School of Medicine; University of California, University of California at San Francisco, Health Sciences Research Institute; University of Warwick, Department of Epidemiology and Biostatistics; School of Public Health; Imperial College London, Department of Hygiene & Epidemiology; University of Ioannina School of Medicine, School of Medicine; University of Nottingham, Department of Medical Statistics and Bioinformatics; Section Molecular Epidemiology; Leiden University Medical Center, Decode Genetics, Department of Epidemiology; Erasmus Medical Center, Respiratory; Inflammation; Autoimmunity Innovative Medicines, California Pacific Medical Center Research Institute, Epidemiology Division; Family Medicine and Public Health Department; University of California, Department of Rheumatology and Department of Clinical Epidemiology; Leiden University Medical Center, University Medical Center Utrecht, Department of Orthopaedics; Leiden University Medical Center, Departments of Medicine and Epidemiology & Public Health; University of Maryland School of Medicine, Geriatrics Research and Education Clinical Center; Baltimore Veterans Administration Medical Center, Department of Epidemiology; Harvard T.H. School of Public Health, Duke Molecular Physiology Institute and Division of Rheumatology; Duke University School of Medicine, Nuffield Department of Orthopaedics; Rheumatology and musculoskeletal sciences; University of Oxford, and Wellcome Trust Sanger Institute
Page Start:: e1006260
Person:: Hart, Deborah J., Rivadeneira, Fernando, Lane, Nancy E., Muir, Kenneth, Evangelou, Evangelos, Doherty, Sally, Castaño-Betancourt, Martha C., Meulenbelt, Ingrid, Boer, Cindy G., Styrkarsdottir, Unnur, Uitterlinden, Andre G., Doherty, Michael, Maciewicz, Rose A., Metrustry, Sarah, Evans, Dan S., den Hollander, Wouter, Barrett-Connor, Elizabeth, Jordan, Joanne M., Kloppenburg, Margreet, van Meurs, Joyce B. J., Lafeber, Floris, Slagboom, Eline P., Nelissen, Rob G. H. H., Yau, Michelle S., Mitchell, Braxton D., Nevitt, Michael C., Ramos, Yolande F. M., Liu, Youfang, Kraaij, Robert, Hofman, Albert, Valdes, Ana M., van Rooij, Jeroen, Kraus, Virginia B., Arden, Nigel, Zeggini, Eleftheria, Zhang, Weiya, and Spector, Tim D.
Rights Statement Label:: In Copyright
Source:: d791sn278

1916. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome

Title Tesim:: Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome
Creator:: Zhao, Xinyu, Li, Ronghui, Dong, Qiping, Zeng, Xin, Wang, Zefeng, Yuan, Xinni, Keles, Sunduz, Chiao, Cassandra, Gao, Yu, Chang, Qiang, and Li, Hongda
Date of publication:: 2016
Abstract Tesim:: Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies.
Resource type:: Article
Affiliation Label Tesim:: Department of Pharmacology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/y94a-yk43
Identifier:: PMCID: PMC4924826, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006129, PMID: 27352031, and Onescience id: 1318c01af29ecbf3eccbe4df80d48bf52a4da735
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 6
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: PSIP1, High-Throughput Nucleotide Sequencing, Gria2, MECP2, Genes, DHX9, Homo sapiens, Synaptic Transmission, Mecp2, Alternative Splicing, RNA Splicing, Exons, Rett Syndrome, GRIA2, Mutation, Phenotype, Methyl-CpG-Binding Protein 2, Dhx9, Mus musculus, Brain, and Therapeutics
Language Label:: English
ORCID:: 0000-0002-5128-4424, , and 0000-0003-4186-0667
Other Affiliation:: Waisman Center; University of Wisconsin-Madison, CMB Training Program; University of Wisconsin-Madison, Department of Statistics; University of Wisconsin-Madison, Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology; CAS-MPG Partner Institute for Computational Biology, Department of Biostatistics and Medical Informatics; University of Wisconsin-Madison, Genetics Training Program; University of Wisconsin-Madison, and Departments of Medical Genetics and Neurology; University of Wisconsin-Madison
Page Start:: e1006129
Person:: Zhao, Xinyu, Li, Ronghui, Dong, Qiping, Zeng, Xin, Wang, Zefeng, Yuan, Xinni, Keles, Sunduz, Chiao, Cassandra, Gao, Yu, Chang, Qiang, and Li, Hongda
Rights Statement Label:: In Copyright
Source:: gt54kt14f

1917. Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly

Title Tesim:: Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly
Creator:: Wang, Zefeng, McMahon, John J., Tsai, Yi-Hsuan, Silver, Debra L., and Mao, Hanqian
Date of publication:: 2016
Abstract Tesim:: The exon junction complex (EJC) is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis and microcephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employ mouse genetics, transcriptomic and proteomic analyses to demonstrate that haploinsufficiency for each of the 3 core EJC components causes microcephaly via converging regulation of p53 signaling. Using a new conditional allele, we first show that Eif4a3 haploinsufficiency phenocopies aberrant neurogenesis and microcephaly of Magoh and Rbm8a mutant mice. Transcriptomic and proteomic analyses of embryonic brains at the onset of neurogenesis identifies common pathways altered in each of the 3 EJC mutants, including ribosome, proteasome, and p53 signaling components. We further demonstrate all 3 mutants exhibit defective splicing of RNA regulatory proteins, implying an EJC dependent RNA regulatory network that fine-tunes gene expression. Finally, we show that genetic ablation of one downstream pathway, p53, significantly rescues microcephaly of all 3 EJC mutants. This implicates p53 activation as a major node of neurodevelopmental pathogenesis following EJC impairment. Altogether our study reveals new mechanisms to help explain how EJC mutations influence neurogenesis and underlie neurodevelopmental disease.
Resource type:: Article
Affiliation Label Tesim:: Department of Pharmacology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/c2fg-t706
Identifier:: Onescience id: 459b926e5f074b316909efdc573cec26c24ab6ae, PMCID: PMC5019403, PMID: 27618312, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1006282
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 9
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: Haploinsufficiency, Nuclear Proteins, Animals, Exons, Multiprotein Complexes, Humans, Proteome, Signal Transduction, RNA-Binding Proteins, Transcriptome, Eukaryotic Initiation Factor-4A, RNA Splicing, Mice, and Neurogenesis
Language Label:: English
ORCID:: and 0000-0003-2107-4300
Other Affiliation:: Department of Molecular Genetics and Microbiology; Duke University School of Medicine, Duke Institute for Brain Sciences; Duke University, Department of Neurobiology; Duke University School of Medicine, and Department of Cell Biology; Duke University School of Medicine
Page Start:: e1006282
Person:: Wang, Zefeng, McMahon, John J., Tsai, Yi-Hsuan, Silver, Debra L., and Mao, Hanqian
Rights Statement Label:: In Copyright
Source:: 44558k26n

1918. Genomic Characterization of Metformin Hepatic Response

Title Tesim:: Genomic Characterization of Metformin Hepatic Response
Creator:: Jones, Stacy L., Laurance, Megan, Luizon, Marcelo R., Ahituv, Nadav, Gallins, Paul J., Yee, Sook Wah, Zhou, Yihui, Wright, Fred, Lin, Lawrence, Etheridge, Amy S., Eckalbar, Walter L., Molony, Cliona, Innocenti, Federico, Wang, Yao, Smith, Robin P., and Giacomini, Kathleen M.
Date of publication:: 2016
Abstract Tesim:: Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.
Resource type:: Article
Affiliation Label Tesim:: Eshelman School of Pharmacy
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/9h8a-yh92
Identifier:: PMID: 27902686, PMCID: PMC5130177, Onescience id: 9b3be178bff749a3c8e76eba95a3b95f4d490daf, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1006449
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 11
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: ATF3, Hepatocytes, Linkage Disequilibrium, DDX10, Clustered Regularly Interspaced Short Palindromic Repeats, Metformin, ATM, EXPH5, AMP-Activated Protein Kinases, Genes, Genes, Regulator, Introns, Haplotypes, Ataxia Telangiectasia, RNA, Activating Transcription Factor 3, Liver, Homo sapiens, Therapeutics, Genome, Gluconeogenesis, and Quantitative Trait Loci
Language Label:: English
ORCID:: , 0000-0001-8219-8660, and 0000-0003-4578-3910
Other Affiliation:: Department of Bioengineering and Therapeutic Sciences; University of California San Francisco, Institute for Human Genetics; University of California San Francisco, Library and Center for Knowledge Management; University of California San Francisco, Department of General Biology; Institute of Biological Sciences; Federal University of Minas Gerais, Bioinformatics Research Center; North Carolina State University, Merck Research Labs; Merck & Co. Inc, and School of Pharmaceutical Sciences; Tsinghua University
Page Start:: e1006449
Person:: Jones, Stacy L., Laurance, Megan, Luizon, Marcelo R., Ahituv, Nadav, Gallins, Paul J., Yee, Sook Wah, Zhou, Yihui, Wright, Fred, Lin, Lawrence, Etheridge, Amy S., Eckalbar, Walter L., Molony, Cliona, Innocenti, Federico, Wang, Yao, Smith, Robin P., and Giacomini, Kathleen M.
Rights Statement Label:: In Copyright
Source:: xk81jr49t

1919. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

Title Tesim:: Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer
Creator:: Jenkins, Mark A., White, Emily, Toth, Reka, Seminara, Daniela, Lemire, Mathieu, Giovannucci, Edward L., Bezieau, Stephane, Thibodeau, Stephen N., Du, Mengmeng, Harrison, Tabitha A., Newcomb, Polly A., Haile, Robert W., Ulrich, Cornelia M., Le Marchand, Loic, Hopper, John L., Chang-Claude, Jenny, Potter, John D., Rudolph, Anja, Lin, Yi, Brenner, Hermann, Hsu, Li, Hayes, Richard B., Chan, Andrew T., Berndt, Sonja I., Bien, Stephanie A., Campbell, Peter T., Slattery, Martha L., Kocarnik, Jonathan, Gallinger, Steven, Küry, Sébastien, Ogino, Shuji, Figueiredo, Jane C., Hutter, Carolyn M., Thornquist, Mark, Jiao, Shuo, Peters, Ulrike, Baron, John A., Wallace, Robert, Gong, Jian, Hudson, Thomas J., Casey, Graham, Jeon, Jihyoun, Hoffmeister, Michael, Duggan, David, Nishihara, Reiko, Schoen, Robert E., Schrotz-King, Petra, and Lindor, Noralane M.
Date of publication:: 2016
Abstract Tesim:: Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10−8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74–0.91]; P = 2.1×10−4) and TT genotypes (OR,0.62 [95% CI, 0.51–0.75]; P = 1.3×10−6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.
Resource type:: Article
Affiliation Label Tesim:: Department of Medicine
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/ywy1-et04
Identifier:: Publisher DOI: https://doi.org/10.1371/journal.pgen.1006296, PMID: 27723779, PMCID: PMC5065124, and Onescience id: b1128809d72ce83662d30dd6e70bbe8c52338794
ISSN:: 1553-7390 and 1553-7404
Journal Issue:: 10
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: Colon, Gastrointestinal Tract, Biology and Life Sciences, Genomics, Computational Biology, Epidemiology, Medicine and Health Sciences, Diet, Behavior, Human Genetics, Genetic Epidemiology, Nutrition, Alcohol Consumption, Anatomy, Oncology, Genetics, Smoking Habits, Habits, Adenomas, Journal Article, Genome-Wide Association Studies, Genome Analysis, Cancers and Neoplasms, Digestive System, Colorectal Cancer, and Gene Expression
Language Label:: English
ORCID:: , 0000-0002-8713-4583, 0000-0001-8084-1608, 0000-0002-4696-3940, and 0000-0002-2397-9480
Other Affiliation:: Melbourne School of Population Health; The University of Melbourne, Public Health Sciences Division; Fred Hutchinson Cancer Research Center, Division of Preventive Oncology; National Center for Tumor Diseases and German Cancer Research Center, Division of Cancer Control and Population Sciences; National Cancer Institute, Ontario Institute for Cancer Research, Channing Division of Network Medicine; Brigham and Women’s Hospital, CHU Nantes; Service de Génétique Médicale, Departments of Laboratory Medicine and Pathology and Laboratory Genetics; Mayo Clinic, Keck School of Medicine; University of Southern California, Huntsman Cancer Institute; University of Utah, Epidemiology Program; University of Hawaii Cancer Center, Division of Cancer Epidemiology; German Cancer Research Center, Centre for Public Health Research; Massey University, Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Division of Epidemiology; New York University School of Medicine, Division of Gastroenterology; Massachusetts General Hospital and Harvard Medical School, Channing Division of Network Medicine; Brigham and Women's Hospital and Harvard Medical School, Division of Cancer Epidemiology and Genetics; National Cancer Institute, Epidemiology Research Program; American Cancer Society, Department of Internal Medicine; University of Utah Health Sciences Center, Department of Surgery; University Health Network Toronto General Hospital, Harvard Medical School; Department of Epidemiology; Harvard School of Public Health, Division of Genomic Medicine; National Human Genome Research Institute, Department of Epidemiology; The University of Iowa, Translational Genomics Research Institute, Dana-Farber Cancer Institute; Harvard School of Public Health, Department of Medicine and Epidemiology; University of Pittsburgh Medical Center, and Department of Health Sciences Research; Mayo Clinic
Page Start:: e1006296
Person:: Jenkins, Mark A., White, Emily, Toth, Reka, Seminara, Daniela, Lemire, Mathieu, Giovannucci, Edward L., Bezieau, Stephane, Thibodeau, Stephen N., Du, Mengmeng, Harrison, Tabitha A., Newcomb, Polly A., Haile, Robert W., Ulrich, Cornelia M., Le Marchand, Loic, Hopper, John L., Chang-Claude, Jenny, Potter, John D., Rudolph, Anja, Lin, Yi, Brenner, Hermann, Hsu, Li, Hayes, Richard B., Chan, Andrew T., Berndt, Sonja I., Bien, Stephanie A., Campbell, Peter T., Slattery, Martha L., Kocarnik, Jonathan, Gallinger, Steven, Küry, Sébastien, Ogino, Shuji, Figueiredo, Jane C., Hutter, Carolyn M., Thornquist, Mark, Jiao, Shuo, Peters, Ulrike, Baron, John A., Wallace, Robert, Gong, Jian, Hudson, Thomas J., Casey, Graham, Jeon, Jihyoun, Hoffmeister, Michael, Duggan, David, Nishihara, Reiko, Schoen, Robert E., Schrotz-King, Petra, and Lindor, Noralane M.
Rights Statement Label:: In Copyright
Source:: g445ck033

1920. Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Title Tesim:: Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD
Creator:: Kanner, Richard E., Ross, James C, El-Bouiez, Adel, Jacobson, Francine, Jacobs, Michael, San Jose Estepar, Raul, Kinney, Gregory, Hobbs, Brian, Austin, John, Thompson, Brad, Yang, Jenny, Maselli-Caceres, Diego, Dransfield, Mark, Bowler, Russell, Billings, Joanne, Lazarus, Stephen C., Bell, Brian, LaVange, Lisa M., Ruiz, Mario E., Parker, Margaret, O’Neal, Wanda K., Adams, Sandra, Adami, Alessandra, Dransfield, Mark T., Swift, Irene, Hanania, Nicola A., Hokanson, John E., Boucher, Richard C., Kelsen, Steven, Lynch, David A., Crapo, James, Fuhrman, Carl, Hersh, Craig P., Rennard, Stephen I., Marchetti, Nathaniel, Curtis, Jeffrey L., Chen, Ting-Huei, Stoel, Berend C, Weissfeld, Joel, Soler, Xavier, Guy, Elizabeth, Tashjian, Joseph, McEvoy, Charlene, Everett, Douglas, Qiao, Dandi, Paine, Robert, Martinez, Carlos H., Schroeder, Joyce, Cho, Michael, Michael Wells, , James Mamary, , Tschirren, Juerg, Oelsner, Elizabeth C., Bhatt, Surya, Steiner, Robert M., Kazerooni, Ella, Washington, Lacey, Pearson, Gregory D.N., Newell, John, Crystal, Ronald G., Rossiter, Harry, Cordova, Francis, Jacobson, Francine L, Kluiber, Alex, Fischer, Hans, Han, MeiLan K., Beaty, Terri, van Ginneken, Bram, Shenoy, Kartik, Alexis, Neil E., Tashkin, Donald P., Hawkins, Gregory A., Regan, Elizabeth, Cornellas, Alejandro, Gouskova, Natalia A., Porszasz, Janos, Al Qaisi, Mustafa, De, Dawn, Yen, Andrew, Barr, R. Graham, Satti, Aditi, Lange, Christoph, Carretta, Elizabeth E., Mann, Tanya, Sciurba, Frank, Lutz, Sharon, D'Souza, Belinda, Wells, J. Michael, Rosiello, Richard, van Rikxoort, Eva, Sharafkhaneh, Amir, Comellas, Alejandro, Budoff, Matthew, Halper-Stromberg, Eitan, Hokanson, John, McAdams, H. Page, Brown, Robert, Scholand, Mary Beth, Allen, Tadashi, Sieren, Jered, Casaburi, Richard, Gray, Teresa, Wilson, Carla, Woodruff, Prescott G., Parulekar, Amit, Cooper, Christopher B., McDonald, Merry-Lynn, Sun, Wei, Quibrera, Pedro Miguel, Nachiappan, Arun, Drummond, M. Bradley, Westney, Gloria, Basta, Patricia V., Han, MeiLan, Wise, Robert, Lynch, David, Horton, Karen, Swift, Alex, Couper, David J., Newell, John D., Santorico, Stephanie, Bandi, Venkata, Kim, Victor, Busch, Robert, Freeman, Christine M., Meyers, Deborah A., Young, Kendra, Wise, Robert A., Nath, Hrudaya, Crapo, James D., Wan, Emily, Hoffman, Eric A., Wendt, Christine, Kechris, Katerina, Wilson, Carla G, Doerschuk, Claire M., Christenson, Stephanie A., Kazerooni, Ella A, Jacobson, Sean, Rozenshtein, Anna, Pratte, Katherine, Cho, Michael H., Kleerup, Eric C., Pace, David, MacIntyre, Neil, Atik, Mustafa, Washko, George, Strand, Matt, Bleecker, Eugene R., Bon, Jessica, Silverman, Edwin K., Begum, Ferdouse, Putcha, Nirupama, Comellas, Alejandro P., Foreman, Marilyn, Laird, Nan, Dass, Chandra, Peters, Stephen P., Hardin, Megan, Thomashow, Byron, Jensen, Robert, Duca, Lindsey, Friedman, Paul, Hastie, Annette T., Guntupalli, Kalpatha, Bailey, William, Anzueto, Antonio, Hersh, Craig, Regan, Elizabeth A., Make, Barry, Alapat, Philip, Ramsdell, Joe, Criner, Gerard J., Hansel, Nadia N., Lan, Charlie, Desai, Parag, Ciccolella, David, Stinson, Douglas, Anderson, Wayne, Boriek, Aladin, Martinez, Fernando J., Castaldi, Peter, Criner, Gerard, Van Beek, Edwin, Chandra, Divay, Pernicano, Perry G., Judy, Philip F, Hetmanski, Jacqueline, Humphries, Stephen, Krishnan, Jerry A., Berkowitz, Eugene, Martinez, Carlos, D'Alonzo, Gilbert, Won, Sungho, Silverman, Edwin, Faino, Anna, Demeo, Dawn, Coxson, Harvey O., Vega-Sanchez, Maria Elena, Hansel, Nadia, and Kaner, Robert J.
Date of publication:: 2016
Abstract Tesim:: Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10−10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.
Resource type:: Article
Affiliation Label Tesim:: Department of Biostatistics, Department of Medicine, Gillings School of Global Public Health, and Department of Epidemiology
Deposit Record:: http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:: http://purl.org/dc/dcmitype/Text
DOI:: https://doi.org/10.17615/zh9p-qj70
Identifier:: PMID: 27532455, PMCID: PMC4988780, Onescience id: 16a0517ba1222cda056c6cbe5e4c2a8dec0c1f8c, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1006011
ISSN:: 1553-7404 and 1553-7390
Journal Issue:: 8
Journal Title:: PLoS Genetics
Journal Volume:: 12
Keyword:: Anatomy, Hematology, Gene Expression, Physical Sciences, Genome Analysis, Biochemistry, Physiology, Body Fluids, Computational Biology, Human Genetics, Emphysema, Meta-Analysis, Genome-Wide Association Studies, Genetics, Biology and Life Sciences, Mathematics, Statistical Methods, Genomics, Blood, Pulmonology, Biomarkers, Chronic Obstructive Pulmonary Disease, Mathematical and Statistical Techniques, Medicine and Health Sciences, and Statistics (Mathematics)
Language Label:: English
ORCID:
Other Affiliation:: Department of Internal Medicine; Division of Pulmonary and Critical Care Medicine; University of Utah, Brigham and Women’s Hospital, Temple University, Epidemiology Core; University of Colorado Anschutz Medical Campus, Columbia University, University of Iowa, University of Texas Health Science Center at San Antonio, University of Alabama, Department of Medicine; Division of Pulmonary Medicine; National Jewish Health, National Jewish Health, University of Minnesota, Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Section of Pulmonary and Critical Care Medicine; Baylor College of Medicine, Baylor College of Medicine, University of Pittsburgh, Channing Division of Network Medicine; Department of Medicine; Brigham and Women's Hospital and Harvard Medical School, Division of Pulmonary and Critical Care Medicine; University of Nebraska, VA Ann Arbor Healthcare System, Division of Pulmonary and Critical Care Medicine; University of Michigan Health System, University of California, Health Partners Research Foundation, Data Coordinating Center and Biostatistics; National Jewish Health, University of Michigan, Duke University Medical Center, Department of Epidemiology; Bloomberg School of Public Health; Johns Hopkins University, Center for Genomics and Personalized Medicine Research; Wake Forest School of Medicine, Department of Epidemiology; Mailman School of Public Health at Columbia University, Department of Medicine; Columbia University Medical Center, Department of Biostatistics and Informatics; Colorado School of Public Health; University of Colorado Anschutz Medical Campus, Reliant Medical Group, Michael E. DeBakey VAMC, Division of Pulmonary and Critical Care Medicine; University of Iowa, Johns Hopkins University, Division of Respiratory and Critical Care Physiology and Medicine; Harbor- University of California at Los Angeles Medical Center, Division of Pulmonary; Critical Care; Sleep and Allergy; Department of Medicine and Cardiovascular Research Institute; University of California San Francisco School of Medicine, Division of Pulmonary; Critical Care and Sleep Medicine; Department of Medicine; Johns Hopkins University School of Medicine, Morehouse School of Medicine, Department of Medicine; Division of Pulmonary; Critical Care and Sleep Medicine; National Jewish Health, Department of Radiology; Division of Physiologic Imaging; University of Iowa Hospitals and Clinics, Division of Pulmonary; Critical Care; Allergy; and Sleep Medicine; Department of Medicine; University of San Francisco Medical Center; University of California San Francisco, Division of Pulmonary and Critical Care Medicine; Department of Medicine; David Geffen School of Medicine; University of California Los Angeles, Department of Medicine; Division of Pulmonary; Critical Care; Allergy and Immunologic Medicine; Wake Forest University School of Medicine, PFT QA Core, Department of Medicine; National Jewish Health, Division of Pulmonary and Critical Care Medicine; Johns Hopkins University School of Medicine, Presbyterian Hospital/Weill Cornell Medical Center, Department of Medicine; Weill Cornell Medical College, Department of Thoracic Medicine and Surgery; Lewis Katz School of Medicine; Temple University, Division of Pulmonary and Critical Care Medicine; Channing Division of Network Medicine; Brigham and Women's Hospital; Harvard Medical School, Department of Medicine; Division of Pulmonary and Critical Care Medicine; Weill Cornell Medical College, and Department of Genetic Medicine; Weill Cornell Medical College
Page Start:: e1006011
Person:: Kanner, Richard E., Ross, James C, El-Bouiez, Adel, Jacobson, Francine, Jacobs, Michael, San Jose Estepar, Raul, Kinney, Gregory, Hobbs, Brian, Austin, John, Thompson, Brad, Yang, Jenny, Maselli-Caceres, Diego, Dransfield, Mark, Bowler, Russell, Billings, Joanne, Lazarus, Stephen C., Bell, Brian, LaVange, Lisa M., Ruiz, Mario E., Parker, Margaret, O’Neal, Wanda K., Adams, Sandra, Adami, Alessandra, Dransfield, Mark T., Swift, Irene, Hanania, Nicola A., Hokanson, John E., Boucher, Richard C., Kelsen, Steven, Lynch, David A., Crapo, James, Fuhrman, Carl, Hersh, Craig P., Rennard, Stephen I., Marchetti, Nathaniel, Curtis, Jeffrey L., Chen, Ting-Huei, Stoel, Berend C, Weissfeld, Joel, Soler, Xavier, Guy, Elizabeth, Tashjian, Joseph, McEvoy, Charlene, Everett, Douglas, Qiao, Dandi, Paine, Robert, Martinez, Carlos H., Schroeder, Joyce, Cho, Michael, Michael Wells, , James Mamary, , Tschirren, Juerg, Oelsner, Elizabeth C., Bhatt, Surya, Steiner, Robert M., Kazerooni, Ella, Washington, Lacey, Pearson, Gregory D.N., Newell, John, Crystal, Ronald G., Rossiter, Harry, Cordova, Francis, Jacobson, Francine L, Kluiber, Alex, Fischer, Hans, Han, MeiLan K., Beaty, Terri, van Ginneken, Bram, Shenoy, Kartik, Alexis, Neil E., Tashkin, Donald P., Hawkins, Gregory A., Regan, Elizabeth, Cornellas, Alejandro, Gouskova, Natalia A., Porszasz, Janos, Al Qaisi, Mustafa, De, Dawn, Yen, Andrew, Barr, R. Graham, Satti, Aditi, Lange, Christoph, Carretta, Elizabeth E., Mann, Tanya, Sciurba, Frank, Lutz, Sharon, D'Souza, Belinda, Wells, J. Michael, Rosiello, Richard, van Rikxoort, Eva, Sharafkhaneh, Amir, Comellas, Alejandro, Budoff, Matthew, Halper-Stromberg, Eitan, Hokanson, John, McAdams, H. Page, Brown, Robert, Scholand, Mary Beth, Allen, Tadashi, Sieren, Jered, Casaburi, Richard, Gray, Teresa, Wilson, Carla, Woodruff, Prescott G., Parulekar, Amit, Cooper, Christopher B., McDonald, Merry-Lynn, Sun, Wei, Quibrera, Pedro Miguel, Nachiappan, Arun, Drummond, M. Bradley, Westney, Gloria, Basta, Patricia V., Han, MeiLan, Wise, Robert, Lynch, David, Horton, Karen, Swift, Alex, Couper, David J., Newell, John D., Santorico, Stephanie, Bandi, Venkata, Kim, Victor, Busch, Robert, Freeman, Christine M., Meyers, Deborah A., Young, Kendra, Wise, Robert A., Nath, Hrudaya, Crapo, James D., Wan, Emily, Hoffman, Eric A., Wendt, Christine, Kechris, Katerina, Wilson, Carla G, Doerschuk, Claire M., Christenson, Stephanie A., Kazerooni, Ella A, Jacobson, Sean, Rozenshtein, Anna, Pratte, Katherine, Cho, Michael H., Kleerup, Eric C., Pace, David, MacIntyre, Neil, Atik, Mustafa, Washko, George, Strand, Matt, Bleecker, Eugene R., Bon, Jessica, Silverman, Edwin K., Begum, Ferdouse, Putcha, Nirupama, Comellas, Alejandro P., Foreman, Marilyn, Laird, Nan, Dass, Chandra, Peters, Stephen P., Hardin, Megan, Thomashow, Byron, Jensen, Robert, Duca, Lindsey, Friedman, Paul, Hastie, Annette T., Guntupalli, Kalpatha, Bailey, William, Anzueto, Antonio, Hersh, Craig, Regan, Elizabeth A., Make, Barry, Alapat, Philip, Ramsdell, Joe, Criner, Gerard J., Hansel, Nadia N., Lan, Charlie, Desai, Parag, Ciccolella, David, Stinson, Douglas, Anderson, Wayne, Boriek, Aladin, Martinez, Fernando J., Castaldi, Peter, Criner, Gerard, Van Beek, Edwin, Chandra, Divay, Pernicano, Perry G., Judy, Philip F, Hetmanski, Jacqueline, Humphries, Stephen, Krishnan, Jerry A., Berkowitz, Eugene, Martinez, Carlos, D'Alonzo, Gilbert, Won, Sungho, Silverman, Edwin, Faino, Anna, Demeo, Dawn, Coxson, Harvey O., Vega-Sanchez, Maria Elena, Hansel, Nadia, and Kaner, Robert J.
Rights Statement Label:: In Copyright
Source:: gb19fb88z