433 results on '"Michael H Cho"'
Search Results
52. Genetics of chronic obstructive pulmonary disease: understanding the pathobiology and heterogeneity of a complex disorder
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Michael H Cho, Brian D Hobbs, and Edwin K Silverman
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Pulmonary and Respiratory Medicine - Published
- 2022
53. Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program
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Xiaowei Hu, Dandi Qiao, Wonji Kim, Matthew Moll, Pallavi P. Balte, Leslie A. Lange, Traci M. Bartz, Rajesh Kumar, Xingnan Li, Bing Yu, Brian E. Cade, Cecelia A. Laurie, Tamar Sofer, Ingo Ruczinski, Deborah A. Nickerson, Donna M. Muzny, Ginger A. Metcalf, Harshavardhan Doddapaneni, Stacy Gabriel, Namrata Gupta, Shannon Dugan-Perez, L. Adrienne Cupples, Laura R. Loehr, Deepti Jain, Jerome I. Rotter, James G. Wilson, Bruce M. Psaty, Myriam Fornage, Alanna C. Morrison, Ramachandran S. Vasan, George Washko, Stephen S. Rich, George T. O’Connor, Eugene Bleecker, Robert C. Kaplan, Ravi Kalhan, Susan Redline, Sina A. Gharib, Deborah Meyers, Victor Ortega, Josée Dupuis, Stephanie J. London, Tuuli Lappalainen, Elizabeth C. Oelsner, Edwin K. Silverman, R. Graham Barr, Timothy A. Thornton, Heather E. Wheeler, Michael H. Cho, Hae Kyung Im, and Ani Manichaikul
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Pulmonary Disease, Chronic Obstructive ,Risk Factors ,Genetics ,Humans ,National Heart, Lung, and Blood Institute (U.S.) ,Transcriptome ,Lung ,Article ,United States ,Genetics (clinical) - Abstract
While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV(1)] and its ratio to forced vital capacity [FEV(1)/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV(1) and FEV(1)/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08–1.43] for PTRS versus 1.10 [0.96–1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p
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- 2022
54. Interstitial Lung Abnormalities, Emphysema, and Spirometry in Smokers
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Akinori Hata, Aravind A. Menon, Jason L. Sanders, Gary M. Hunninghake, George R. Washko, Samuel Y. Ash, Rachel K. Putman, Takuya Hino, Auyon J. Ghosh, David A. Lynch, Hiroto Hatabu, Ivan O. Rosas, Edwin K. Silverman, Michael H. Cho, and Mizuki Nishino
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Pulmonary and Respiratory Medicine ,Spirometry ,medicine.medical_specialty ,Pulmonary Fibrosis ,Critical Care and Intensive Care Medicine ,FEV1/FVC ratio ,Usual interstitial pneumonia ,Internal medicine ,Pulmonary fibrosis ,medicine ,Humans ,Lung volumes ,Lung ,Emphysema ,COPD ,Smokers ,medicine.diagnostic_test ,business.industry ,Interstitial lung disease ,respiratory system ,medicine.disease ,Combined pulmonary fibrosis and emphysema ,respiratory tract diseases ,Pulmonary Emphysema ,Cardiology ,Respiratory System Abnormalities ,Cardiology and Cardiovascular Medicine ,business - Abstract
Most pulmonary conditions reduce FVC, but studies of patients with combined pulmonary fibrosis and emphysema demonstrate that reductions in FVC are less than expected when these two conditions coexist clinically.Do interstitial lung abnormalities (ILAs), chest CT imaging findings that may suggest an early stage of pulmonary fibrosis in individuals with undiagnosed disease, affect the association between emphysema and FVC?Measures of ILA and emphysema were available for 9,579 and 5,277 participants from phases 1 (2007-2011) and 2 (2012-2016) of the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study (COPDGene), respectively. ILA were defined by Fleischner Society guidelines. Adjusted linear regression models were used to assess the associations and interactions among ILA, emphysema, measures of spirometry, and lung function.ILA were present in 528 (6%) and 580 (11%) of participants in phases 1 and 2 of COPDGene, respectively. ILA modified the association between emphysema and FVC (P .0001 for interaction) in both phases. In phase 1, in those without ILA, a 5% increase in emphysema was associated with a reduction in FVC (-110 mL; 95% CI, -121 to -100 mL; P .0001); however, in those with ILA, it was not (-11 mL; 95% CI, -53 to 31; P = .59). In contrast, no interaction was found between ILA and emphysema on total lung capacity or on diffusing capacity of carbon monoxide.The presence of ILA attenuates the reduction in FVC associated with emphysema.
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- 2022
55. Association of clonal hematopoiesis with chronic obstructive pulmonary disease
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Stephen S. Rich, Donna Neuberg, Michael H. Cho, Bing Yu, Matthew Leventhal, George T. O'Connor, Ani Manichaikul, Weiwei Shi, Lynette M. Sholl, Michael C. Honigberg, Abhishek Niroula, Benjamin L. Ebert, Joselyn Rojas-Quintero, R. Graham Barr, Matthew Moll, Stephanie J. London, L. Adrienne Cupples, Siddhartha Jaiswal, Elizabeth C. Oelsner, Brittany E Sandoval, Pradeep Natarajan, Brian E. Cade, Peter van Galen, Susan Redline, Yohannes Tesfaigzi, Christopher J. Gibson, Stephanie M. Gogarten, COPDGene Study Investigators, Deepti Jain, Adolfo Correa, Bruce D. Levy, Sina A. Gharib, Peter Miller, Kaushik Viswanathan, Caroline A. Owen, Edwin K. Silverman, Lillian Werner, Jerome I. Rotter, Dandi Qiao, Brian C. Miller, Adam S. Sperling, Leslie A. Lange, Alexander G. Bick, Marie McConkey, and Vasan S. Ramachandran
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Male ,Oncology ,medicine.medical_specialty ,Somatic cell ,Immunology ,Pulmonary disease ,Inflammation ,Disease ,Biochemistry ,Mice ,Pulmonary Disease, Chronic Obstructive ,Risk Factors ,Internal medicine ,Exome Sequencing ,Odds Ratio ,medicine ,Animals ,Humans ,Exome sequencing ,COPD ,business.industry ,Smoking ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Confidence interval ,Haematopoiesis ,Female ,Clonal Hematopoiesis ,medicine.symptom ,business - Abstract
Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, −5.7%; adjusted 95% CI, −8.8% to −2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.
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- 2022
56. Development of a Blood-based Transcriptional Risk Score for Chronic Obstructive Pulmonary Disease
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Matthew Moll, Adel Boueiz, Auyon J. Ghosh, Aabida Saferali, Sool Lee, Zhonghui Xu, Jeong H. Yun, Brian D. Hobbs, Craig P. Hersh, Don D. Sin, Ruth Tal-Singer, Edwin K. Silverman, Michael H. Cho, Peter J. Castaldi, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Jacqueline Hetmanski, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Kendra A. Young, Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, Susan Murray, Xavier Soler, Russell P. Bowler, Katerina Kechris, and Farnoush Banaei-Kashani
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Pulmonary and Respiratory Medicine ,COPD ,Framingham Risk Score ,business.industry ,Pulmonary disease ,Critical Care and Intensive Care Medicine ,medicine.disease ,Bioinformatics ,Peripheral blood ,respiratory tract diseases ,Transcriptome ,Gene expression ,medicine ,Polygenic risk score ,business - Abstract
Rationale: The ability of peripheral blood biomarkers to assess COPD risk and progression is unknown. Genetics and gene expression may capture important aspects of COPD-related biology that predict...
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- 2022
57. An Integrative Genomic Strategy Identifies sRAGE as a Causal and Protective Biomarker of Lung Function
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Edwin K. Silverman, Shih-Jen Hwang, Paul Courchesne, Daniel Levy, George R. Washko, Josée Dupuis, Joshua Keefe, George T. O'Connor, Gha Young Lee, Joseph P. Mizgerd, Chen Yao, and Michael H. Cho
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Adult ,Lung Diseases ,Male ,Pulmonary and Respiratory Medicine ,Quantitative Trait Loci ,Receptor for Advanced Glycation End Products ,Vital Capacity ,Single-nucleotide polymorphism ,Genome-wide association study ,Quantitative trait locus ,Critical Care and Intensive Care Medicine ,Bioinformatics ,Framingham Heart Study ,Forced Expiratory Volume ,Mendelian randomization ,Humans ,SNP ,Medicine ,Lung ,Aged ,Genetic association ,business.industry ,Genomics ,Mendelian Randomization Analysis ,Middle Aged ,Protective Factors ,Respiratory Function Tests ,Biomarker (cell) ,Female ,Cardiology and Cardiovascular Medicine ,business ,Genome-Wide Association Study - Abstract
Background There are few clinically useful circulating biomarkers of lung function and lung disease. We hypothesized that genome-wide association studies (GWAS) of circulating proteins in conjunction with GWAS of pulmonary traits represents a clinically relevant approach to identifying causal proteins and therapeutically useful insights into mechanisms related to lung function and disease. Study Question Can an integrative genomic strategy using GWAS of plasma soluble receptor for advanced glycation end-products (sRAGE) levels in conjunction with GWAS of lung function traits identify putatively causal relations of sRAGE to lung function? Study Design and Methods Plasma sRAGE levels were measured in 6,861 Framingham Heart Study participants and GWAS of sRAGE was conducted to identify protein quantitative trait loci (pQTL), including cis-pQTL variants at the sRAGE protein-coding gene locus (AGER). We integrated sRAGE pQTL variants with variants from GWAS of lung traits. Colocalization of sRAGE pQTL variants with lung trait GWAS variants was conducted, and Mendelian randomization was performed using sRAGE cis-pQTL variants to infer causality of sRAGE for pulmonary traits. Cross-sectional and longitudinal protein-trait association analyses were conducted for sRAGE in relation to lung traits. Results Colocalization identified shared genetic signals for sRAGE with lung traits. Mendelian randomization analyses suggested protective causal relations of sRAGE to several pulmonary traits. Protein-trait association analyses demonstrated higher sRAGE levels to be cross-sectionally and longitudinally associated with preserved lung function. Interpretation sRAGE is produced by type I alveolar cells, and it acts as a decoy receptor to block the inflammatory cascade. Our integrative genomics approach provides evidence for sRAGE as a causal and protective biomarker of lung function, and the pattern of associations is suggestive of a protective role of sRAGE against restrictive lung physiology. We speculate that targeting the AGER/sRAGE axis may be therapeutically beneficial for the treatment and prevention of inflammation-related lung disease.
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- 2022
58. Identifying COPD subtypes using multi-trait genetics
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Andrey Ziyatdinov, Brian D. Hobbs, Samir Kanaan-Izquierdo, Matthew Moll, Phuwanat Sakornsakolpat, Nick Shrine, Jing Chen, Kijoung Song, Russell P. Bowler, Peter J. Castaldi, Martin D. Tobin, Peter Kraft, Edwin K. Silverman, Hanna Julienne, Hugues Aschard, and Michael H. Cho
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Article - Abstract
Chronic Obstructive Pulmonary Disease (COPD) has a simple physiological diagnostic criterion but a wide range of clinical characteristics. The mechanisms underlying this variability in COPD phenotypes are unclear. To investigate the potential contribution of genetic variants to phenotypic heterogeneity, we examined the association of genome-wide associated lung function, COPD, and asthma variants with other phenotypes using phenome-wide association results derived in the UK Biobank. Our clustering analysis of the variants-phenotypes association matrix identified three clusters of genetic variants with different effects on white blood cell counts, height, and body mass index (BMI). To assess the potential clinical and molecular effects of these groups of variants, we investigated the association between cluster-specific genetic risk scores and phenotypes in the COPDGene cohort. We observed differences in steroid use, BMI, lymphocyte counts, chronic bronchitis, and differential gene and protein expression across the three genetic risk scores. Our results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD.
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- 2023
59. Integrating Genetics, Transcriptomics, and Proteomics in Lung Tissue to Investigate COPD
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Yu-Hang Zhang, Michael H Cho, Jarrett D Morrow, Peter J Castaldi, Craig P. Hersh, Mukul K Midha, Michael R Hoopmann, Sharon M Lutz, Robert L Moritz, and Edwin K. Silverman
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Pulmonary and Respiratory Medicine ,Clinical Biochemistry ,Cell Biology ,Molecular Biology - Published
- 2023
60. Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in Two TOPMed Cohorts
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Michael H. Cho, Robert E. Gerszten, Brian D. Hobbs, Clary B. Clish, Scott T. Weiss, Juan C. Celedón, Michael J. McGeachie, Craig E. Wheelock, Jessica Lasky-Su, Su H. Chu, Rachel S. Kelly, Kevin M. Mendez, and Mengna Huang
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Pulmonary and Respiratory Medicine ,Male ,Adolescent ,business.industry ,Reproducibility of Results ,Computational biology ,Original Articles ,Critical Care and Intensive Care Medicine ,medicine.disease ,Asthma ,Cohort Studies ,Molecular classification ,Metabolomics ,Phenotype ,medicine ,Humans ,Female ,business ,Child ,Lung ,Lung function - Abstract
RATIONALE: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). OBJECTIVES: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. METHODS: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. MEASUREMENTS AND MAIN RESULTS: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10(−5)) and postbronchodilator (p-ANOVA = 1.8 × 10(−5)) FEV(1)/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. CONCLUSIONS: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.
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- 2023
61. X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study
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Lystra P Hayden, Brian D Hobbs, Robert Busch, Michael H Cho, Ming Liu, Camila M Lopes-Ramos, David A Lomas, Per Bakke, Amund Gulsvik, Edwin K Silverman, James D Crapo, Terri H Beaty, Nan M Laird, Christoph Lange, and Dawn L DeMeo
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respiratory tract diseases - Abstract
Background The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations. Methods Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case–control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses. Results Among 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV1/FVC ($$\beta$$ β 0.020, SE 0.004, p 4.97 × 10–08), with suggestive evidence of association with FEV1 ($$\beta$$ β 0.092, SE 0.018, p 3.40 × 10–07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions. Conclusions This investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology. Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease.
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- 2023
62. Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants
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Anna L. Peljto, Rachel Z. Blumhagen, Avram D. Walts, Jonathan Cardwell, Julia Powers, Tamera J. Corte, Joanne L. Dickinson, Ian Glaspole, Yuben P. Moodley, Martina Koziar Vasakova, Elisabeth Bendstrup, Jesper R. Davidsen, Raphael Borie, Bruno Crestani, Philippe Dieude, Francesco Bonella, Ulrich Costabel, Gunnar Gudmundsson, Seamas C. Donnelly, Jim Egan, Michael T. Henry, Michael P. Keane, Marcus P. Kennedy, Cormac McCarthy, Aoife N. McElroy, Joshua A. Olaniyi, Katherine M. A. O’Reilly, Luca Richeldi, Paolo M. Leone, Venerino Poletti, Francesco Puppo, Sara Tomassetti, Valentina Luzzi, Nurdan Kokturk, Nesrin Mogulkoc, Christine A. Fiddler, Nikhil Hirani, R. Gisli Jenkins, Toby M. Maher, Philip L. Molyneaux, Helen Parfrey, Rebecca Braybrooke, Timothy S. Blackwell, Peter D. Jackson, Steven D. Nathan, Mary K. Porteous, Kevin K. Brown, Jason D. Christie, Harold R. Collard, Oliver Eickelberg, Elena E. Foster, Kevin F. Gibson, Marilyn Glassberg, Daniel J. Kass, Jonathan A. Kropski, David Lederer, Angela L. Linderholm, Jim Loyd, Susan K. Mathai, Sydney B. Montesi, Imre Noth, Justin M. Oldham, Amy J. Palmisciano, Cristina A. Reichner, Mauricio Rojas, Jesse Roman, Neil Schluger, Barry S. Shea, Jeffrey J. Swigris, Paul J. Wolters, Yingze Zhang, Cecilia M. A. Prele, Juan I. Enghelmayer, Maria Otaola, Christopher J. Ryerson, Mauricio Salinas, Martina Sterclova, Tewodros H. Gebremariam, Marjukka Myllärniemi, Roberto G. Carbone, Haruhiko Furusawa, Masaki Hirose, Yoshikazu Inoue, Yasunari Miyazaki, Ken Ohta, Shin Ohta, Tsukasa Okamoto, Dong Soon Kim, Annie Pardo, Moises Selman, Alvaro U. Aranda, Moo Suk Park, Jong Sun Park, Jin Woo Song, Maria Molina-Molina, Lurdes Planas-Cerezales, Gunilla Westergren-Thorsson, Albert V. Smith, Ani W. Manichaikul, John S. Kim, Stephen S. Rich, Elizabeth C. Oelsner, R. Graham Barr, Jerome I. Rotter, Josee Dupuis, George O’Connor, Ramachandran S. Vasan, Michael H. Cho, Edwin K. Silverman, Marvin I. Schwarz, Mark P. Steele, Joyce S. Lee, Ivana V. Yang, Tasha E. Fingerlin, and David A. Schwartz
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Pulmonary and Respiratory Medicine ,Whole Genome Sequencing ,Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO ,Critical Care and Intensive Care Medicine ,Interstitial Lung Disease ,TOPMed ,Telomerase ,Genetic Association Studies - Abstract
Rationale: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.
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- 2023
63. Multiethnic genome-wide and HLA association study of total serum IgE level
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Lynda C. Schneider, Craig P. Hersh, Caitlin P. McHugh, Amy S. Paller, Tissa Hata, Dandi Qiao, Ingo Ruczinski, Harold Watson, Nicholas Rafaels, Camila Alexandrina Figueiredo, Edwin K. Silverman, Scott T. Weiss, Luis Caraballo, Victor E. Ortega, Donald Y.M. Leung, Monica Campbell, Nirupama Putcha, Karine A. Viaud-Martinez, George T. O'Connor, Michelle Daya, Priyadarshini Kachroo, Nadia N. Hansel, Emma Guttman-Yassky, Corey Cox, Terri H. Beaty, Gloria David, Nathalie Acevedo, Sameer Chavan, Rasika A. Mathias, Jon M. Hanifin, Jessica Lasky-Su, Adrienne Cupples, Mark K. Slifka, Michael H. Cho, Richard L. Gallo, Eugene R. Bleecker, Deborah A. Meyers, Xingnan Li, Carole Ober, Meher Preethi Boorgula, Peck Y. Ong, Robert M. Reed, Ramachandran S. Vasan, Jonathan M. Spergel, Kathleen C. Barnes, Jennifer Knight-Madden, and Lisa A. Beck
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Adult ,Male ,Linkage disequilibrium ,Adolescent ,Genotype ,Immunology ,Genome-wide association study ,Disease ,Human leukocyte antigen ,Biology ,Genome ,Article ,Dermatitis, Atopic ,Young Adult ,Gene Frequency ,HLA-A2 Antigen ,Ethnicity ,HLA-DQ beta-Chains ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,Allele ,Child ,Aged ,Genetic association ,Genetics ,Whole Genome Sequencing ,Immunoglobulin E ,Middle Aged ,Asthma ,United States ,Child, Preschool ,Female ,National Heart, Lung, and Blood Institute (U.S.) ,Genome-Wide Association Study - Abstract
BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article’s Online Repository at www.jacionline.org. RESULTS: We identified six loci at genome-wide significance (P
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- 2021
64. Prevalence and mortality associations of interstitial lung abnormalities in rheumatoid arthritis within a multicenter prospective cohort of smokers
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Gregory C McDermott, Keigo Hayashi, Kazuki Yoshida, Matthew Moll, Michael H Cho, Tracy J Doyle, Gregory L Kinney, Paul F Dellaripa, Rachel K Putman, Raul San Jose Estepar, Akinori Hata, Takuya Hino, Tomoyuki Hida, Masahiro Yanagawa, Mizuki Nishino, George Washko, Elizabeth Regan, Hiroto Hatabu, Gary M Hunninghake, Edwin K Silverman, and Jeffrey A Sparks
- Abstract
ObjectivesInvestigate the prevalence and mortality impact of interstitial lung abnormalities (ILA) in rheumatoid arthritis (RA) and non-RA comparators.MethodsWe analyzed associations between ILA, RA, and mortality in COPDGene, a multicenter prospective cohort study of current or former smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution computed tomography (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate, or absent as well as fibrotic or nonfibrotic ILA subtype. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression.ResultsWe identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders including genetics, smoking, and other lifestyle factors, ILA were more common among those with RA compared to non-RA (OR 4.76 95%CI 2.54 to 8.92). RA with ILA or indeterminate for ILA was associated with higher mortality compared to non-RA without ILA (HR 3.16, 95%CI 2.11 to 4.74) and RA cases without ILA (HR 3.02, 95%CI 1.36 to 6.75).ConclusionsRA was associated with ILA and this persisted after adjustment for smoking and genetic/lifestyle risk factors. RA with ILA in chronic heavy smokers had 3-fold increased mortality, emphasizing the importance of further screening and treatment strategies for subclinical ILD in RA.KEY MESSAGESWhat is already known on this topicUp to a third of patients with rheumatoid arthritis (RA) may have evidence of subclinical interstitial lung abnormalities on computed tomography (CT) scans of the chest.Cigarette smoking and theMUC5Bpromoter variant are known risk factors for RA-associated interstitial lung disease.What this study addsWe found that 17% of RA patients had subclinical interstitial lung abnormalities. RA had 4-fold higher odds of interstitial lung abnormalities than non-RA comparators, adjusted for smoking, theMUC5Bpromoter variant, and other factors.Participants with RA and no interstitial lung abnormalities were not at increased mortality risk while those with interstitial lung abnormalities or indeterminate for ILA had a three-fold increased risk of mortality compared to RA and non-RA patients without interstitial lung abnormalities.How this study might affect research, practice or policyThe presence of subclinical interstitial lung abnormalities confers significant mortality risk in RA and emphasizes the need to establish the clinical utility of screening, prevention, and treatment strategies targeting subclinical lung disease.
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- 2022
65. Who Modifies the Modifiers: A High-Resolution View of the Genetic Modifiers of Cystic Fibrosis
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Sean Kalra and Michael H. Cho
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Pulmonary and Respiratory Medicine ,Critical Care and Intensive Care Medicine - Published
- 2023
66. Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program
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Nicholas L. Smith, James A. Perry, Cecelia A. Laurie, Nancy J. Cox, Gonçalo R. Abecasis, Jerome I. Rotter, Laura Almasy, Zhe Wang, Michelle Daya, Yun Li, Eric Jorgenson, Adolfo Correa, Jai G. Broome, Nancy Min, Lisa R. Yanek, Alanna C. Morrison, Lynette Ekunwe, Debby Ngo, Victor E. Ortega, Klaudia Walter, John Blangero, Laura M. Raffield, Corey Cox, Terri H. Beaty, Deborah A. Meyers, Hua Tang, Marsha M. Wheeler, Kari E. North, Xue Zhong, Yann Ilboudo, Andrew D. Johnson, Caitlin P. McHugh, Jeffrey R. O'Connell, Ming-Huei Chen, Russell P. Tracy, Ramachandran S. Vasan, Nathan Pankratz, Joshua P. Lewis, Dawn L. DeMeo, Linda M. Polfus, Leslie A. Lange, Nancy L. Heard-Costa, Robert C. Kaplan, Meher Preethi Boorgula, Robert E. Gerszten, Albert V. Smith, Paul L. Auer, Sameer Chavan, Jennifer A. Brody, Charles Kooperberg, Michael Preuss, David C. Glahn, Rasika A. Mathias, Paul S. de Vries, Jonathon Rosen, Anna V. Mikhaylova, Joe Zein, Eric Boerwinkle, Nathalie Chami, Kathleen C. Barnes, Joanne E. Curran, Edwin K. Silverman, Matthew P. Conomos, Stephen S. Rich, Nicole Soranzo, Heather M. Highland, Michael H. Cho, Donald M. Lloyd-Jones, Myriam Fornage, Guillaume Lettre, Tyne W Miller-Fleming, Kathleen A. Ryan, Thomas W. Blackwell, Bruce M. Psaty, Lewis C. Becker, Nauder Faraday, Hélène Choquet, Alexander P. Reiner, Adam S. Butterworth, Kousik Kundu, Deepti Jain, Timothy A. Thornton, Brian D. Hobbs, Braxton D. Mitchell, Jee-Young Moon, Lifang Hou, Ani Manichaikul, Praveen Surendran, Suraj S. Nongmaithem, Quan Sun, Bingshan Li, Deborah A. Nickerson, and Ruth J. F. Loos
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Proteome ,Quantitative Trait Loci ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,Dermatitis, Atopic ,Pulmonary Disease, Chronic Obstructive ,Leukocytes ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,Genetics (clinical) ,X chromosome ,Genetic association ,Whole genome sequencing ,Autosome ,Whole Genome Sequencing ,Genome, Human ,Monocyte ,Prognosis ,Asthma ,United Kingdom ,United States ,Phenotype ,medicine.anatomical_structure ,National Heart, Lung, and Blood Institute (U.S.) ,Biomarkers ,Imputation (genetics) ,Genome-Wide Association Study - Abstract
Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
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- 2021
67. A polygenic risk score for asthma in a large racially diverse population
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Sharon M. Lutz, Carlos Iribarren, Rachel S. Kelly, Ann Chen Wu, Kelan G. Tantisira, Michael J. McGeachie, Eric Jorgenson, Michael H. Cho, Phuwanat Sakornsakolpat, Joanne E. Sordillo, Amber Dahlin, Jessica Lasky-Su, and Matthew Moll
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Male ,medicine.medical_specialty ,business.industry ,Immunology ,Ethnic group ,Genome-wide association study ,Hispanic or Latino ,Odds ratio ,Disease ,medicine.disease ,Article ,Asthma ,Asian People ,Risk Factors ,Cohort ,Epidemiology ,Humans ,Immunology and Allergy ,Medicine ,Female ,Genetic Predisposition to Disease ,Polygenic risk score ,business ,Demography - Abstract
BACKGROUND Polygenic risk scores (PRSs) will have important utility for asthma and other chronic diseases as a tool for predicting disease incidence and subphenotypes. OBJECTIVE We utilized findings from a large multiancestry GWAS of asthma to compute a PRS for asthma with relevance for racially diverse populations. METHODS We derived two PRSs for asthma using a standard approach (based on genome-wide significant variants) and a lasso sum regression approach (allowing all genetic variants to potentially contribute). We used data from the racially diverse Kaiser Permanente GERA cohort (68 638 non-Hispanic Whites, 5874 Hispanics, 6870 Asians and 2760 Blacks). Race was self-reported by questionnaire. RESULTS For the standard PRS, non-Hispanic Whites showed the highest odds ratio for a standard deviation increase in PRS for asthma (OR = 1.16 (95% CI 1.14-1.18)). The standard PRS was also associated with asthma in Hispanic (OR = 1.12 (95% CI 1.05-1.19)) and Asian (OR = 1.10 (95% CI 1.04-1.17)) subjects, with a trend towards increased risk in Blacks (OR = 1.05 (95% CI 0.97-1.15)). We detected an interaction by sex, with men showing a higher risk of asthma with an increase in PRS as compared to women. The lasso sum regression-derived PRS showed stronger associations with asthma in non-Hispanic White subjects (OR = 1.20 (95% CI 1.18-1.23)), Hispanics (OR = 1.17 (95% 1.10-1.26)), Asians (OR = 1.18 (95% CI 1.10-1.27)) and Blacks (OR = 1.10 (95% CI 0.99-1.22)). CONCLUSION Polygenic risk scores across multiple racial/ethnic groups were associated with increased asthma risk, suggesting that PRSs have potential as a tool for predicting disease development.
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- 2021
68. Novel Privacy Considerations for Large Scale Proteomics
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Andrew C. Hill, Elizabeth M. Litkowski, Ani Manichaikul, Bing Yu, Betty A. Gorbet, Leslie Lange, Katherine A. Pratte, Katerina J. Kechris, Matthew DeCamp, Marilyn Coors, Victor E. Ortega, Stephen S. Rich, Jerome I. Rotter, Robert E. Gerzsten, Clary B. Clish, Jeffrey Curtis, Xiaowei Hu, Debby Ngo, Wanda K. O'Neal, Deborah Meyers, Eugene Bleecker, Brian D. Hobbs, Michael H. Cho, Farnoush Banaei-Kashani, Claire Guo, and Russell Bowler
- Abstract
Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to match proteomes to genomes for 2,812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We were able to correctly match 90%-95% of proteomes to their correct genome and for 95%-99% we could match the proteome to the 1% most likely genome. The accuracy of matching in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. When serial proteomes are available, the matching algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1,000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable.
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- 2022
69. Genetic Regulators of Sputum Mucin Concentration and Their Associations with COPD Phenotypes
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Eric Van Buren, Giorgia Radicioni, Sarah Lester, Wanda K. O’Neal, Hong Dang, Silva Kasela, Suresh Garudadri, Jeffrey L. Curtis, Meilan Han, Jerry A. Krishnan, Emily S. Wan, Edwin K. Silverman, Annette Hastie, Victor E. Ortega, Tuuli Lappalainen, Stephanie A. Christenson, Yun Li, Michael H. Cho, Mehmet Kesimer, and Samir N. P. Kelada
- Abstract
Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n=708 for total mucin, n=215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n=822-1300). Replication analysis was conducted using data from COPDGene (n =5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR=1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB.Author SummaryChronic obstructive pulmonary disease (COPD) is characterized by presence of emphysema and/or chronic bronchitis. Excessive mucus production is a defining phenotype of chronic bronchitis, and is associated with several important features of COPD, including exacerbations and loss of lung function. Recent studies have demonstrated that the amount of mucus produced in COPD patients is an important marker of disease state. We investigated whether common genetic variants are associated with the concentration of two key proteins in mucus, MUC5AC and MUC5B, and whether the variants we identified are also associated with COPD outcomes. We identified multiple genetic variants that were associated with MUC5AC or MUC5B concentration. The strongest association we detected, for MUC5B on chromosome 11, was also associated with features of COPD, including chronic bronchitis and acute exacerbations, in one COPD study population but not another. Results from a much larger study, the UK Biobank, indicate that this variant is associated with chronic mucus production and chronic cough, which are key features of chronic bronchitis. Thus, we conclude that the concentration of key proteins in mucus are influenced by genetic variation, and that a variant on chromosome 11 that affects MUC5B may in turn alter COPD outcomes.
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- 2022
70. Leveraging deep-learning on raw spirograms to improve genetic understanding and risk scoring of COPD despite noisy labels
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Justin Cosentino, Babak Behsaz, Babak Alipanahi, Zachary R. McCaw, Davin Hill, Tae-Hwi Schwantes-An, Dongbing Lai, Andrew Carroll, Brian D. Hobbs, Michael H. Cho, Cory Y. McLean, and Farhad Hormozdiari
- Abstract
Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is highly heritable. While COPD is clinically defined by applying thresholds to summary measures of lung function, a quantitative liability score has more power to identify new genetic signals. Here we train a deep convolutional neural network on noisy self-reported and ICD-based labels to predict COPD case/control status from high-dimensional raw spirograms and use the model predictions as a liability score. The machine-learning-based (ML-based) liability score accurately discriminates COPD cases and controls (AUROC = 0.82 ± 0.01) and COPD-related hospitalization (AUROC = 0.89 ± 0.01) without any domain-specific knowledge. Moreover, the ML-based liability score is associated with overall survival (Hazard ratio = 1.22 ± 0.01; P ≤ 2 × 10−16) and exacerbation events (R2 = 0.10 ± 0.01; P ≤ 4 × 10−101). A genome-wide association study on the ML-based liability score replicates existing COPD and lung function loci, but also identifies 67 new loci. Thirty-eight of these have supportive evidence in independent datasets, including a locus near LTBR. We demonstrate the biological plausibility of the novel variants through enrichment analyses, phenome-wide association studies, and generalizability of COPD prediction in multiple datasets. These results provide an example of the potential to improve genetic discovery of disease-relevant variants by training deep neural networks to predict noisy labels from high-dimensional raw data.
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- 2022
71. Heterozygosity of the Alpha 1‐Antitrypsin Pi*Z Allele and Risk of Liver Disease
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Jiangyuan Liu, Dandi Qiao, Brian D. Hobbs, Aaron Hakim, Jessica Lasky-Su, Michael H. Cho, Z. Gordon Jiang, Silvia Vilarinho, Matthew Moll, and Edwin K. Silverman
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medicine.medical_specialty ,education.field_of_study ,Cirrhosis ,Hepatology ,business.industry ,Population ,Original Articles ,Odds ratio ,RC799-869 ,Diseases of the digestive system. Gastroenterology ,medicine.disease ,Loss of heterozygosity ,Liver disease ,Endocrinology ,Internal medicine ,Medicine ,Original Article ,Allele ,Risk factor ,business ,education ,TM6SF2 - Abstract
The serpin family A member 1 (SERPINA1) Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1‐antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population‐based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital‐based cohort. We also examined variants associated with liver disease and assessed for gene–gene and gene–environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53; P = 1.1×10−04); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8; P = 1.8 × 10−09). The OR for cirrhosis of the Z allele was comparable to that of well‐established genetic variants, including patatin‐like phospholipase domain containing 3 (PNPLA3) I148M (OR, 1.48; P = 1.1 × 10−22) and transmembrane 6 superfamily member 2 (TM6SF2) E167K (OR, 1.34; P = 2.6 × 10−06). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT; P = = 4.6 × 10−46), aspartate aminotransferase (AST; P = 2.2 × 10−27), alkaline phosphatase (P = 3.3 × 10−43), gamma‐glutamyltransferase (P = 1.2 × 10−05), and total bilirubin (P = 6.4 × 10−06); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT (P interaction = 0.021) and AST (P interaction = 0.0040), suggesting a gene–environment interaction. Finally, we demonstrated genetic interactions between variants in PNPLA3, TM6SF2, and hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13); there was no evidence of epistasis between the Z allele and these variants. Conclusion: SERPINA1 Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.
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- 2021
72. A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease
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Josée Dupuis, Victoria E. Jackson, Hanfei Xu, Brian D. Hobbs, Edwin K. Silverman, Michael H. Cho, Megan L. Grove, Jennifer N. Nguyen, Jiangyuan Liu, George T. O'Connor, Natalie Terzikhan, Ani Manichaikul, Patricia A. Cassano, Colleen M. Sitlani, Buhm Han, Ian P. Hall, Bing Yu, Sina A. Gharib, Lies Lahousse, Louise V. Wain, Traci M. Bartz, Christopher J. Benway, R. Graham Barr, Phuwanat Sakornsakolpat, Guy Brusselle, Stephanie J. London, Kun Hee Kim, Martin D. Tobin, Matthew Moll, Jinkyeong Park, Woo Jin Kim, Bonnie K Patchen, Stephen S. Rich, and Epidemiology
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0301 basic medicine ,Nonsynonymous substitution ,Pulmonary and Respiratory Medicine ,EXPRESSION ,Genetic Markers ,Physiology ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,chronic obstructive pulmonary disease ,GENETIC ASSOCIATION ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,DESIGN ,Meta-Analysis as Topic ,Physiology (medical) ,Medicine and Health Sciences ,genomics ,COPD ,Humans ,Exome ,Genetic Predisposition to Disease ,exon ,Allele ,GENOME-WIDE ASSOCIATION ,Genotyping ,Genetic association ,Genetics ,ZINC-FINGER PROTEIN ,Odds ratio ,Cell Biology ,GENOTYPE ,Minor allele frequency ,LUNG-FUNCTION ,functional ,030104 developmental biology ,030228 respiratory system ,ATHEROSCLEROSIS ,Gene Expression Regulation ,SMOKING ,exome ,Genome-Wide Association Study ,Research Article - Abstract
Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( P < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B ( GSDMB) splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, P = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 ( CCHCR1), a gene involved in regulating cell proliferation, were associated with COPD (both P < 0.0001). The SERPINA1 Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17–1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.
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- 2021
73. Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors
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Dawn L. DeMeo, Edwin K. Silverman, Brian D. Hobbs, Jingzhou Zhang, Michael H. Cho, R. Chad Wade, J. Michael Wells, and Barry J. Make
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Male ,Secondary Polycythemia ,medicine.medical_treatment ,Severity of Illness Index ,Hypoxemia ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,DLCO ,Risk Factors ,Diffusing capacity ,Oxygen therapy ,hemic and lymphatic diseases ,Prevalence ,Medicine ,030212 general & internal medicine ,Prospective Studies ,Hypoxia ,Aged, 80 and over ,COPD ,Carbon Monoxide ,medicine.diagnostic_test ,Middle Aged ,Pulmonary Emphysema ,Female ,medicine.symptom ,Research Article ,Pulmonary and Respiratory Medicine ,Spirometry ,medicine.medical_specialty ,Polycythemia ,Lower risk ,Cigarette Smoking ,03 medical and health sciences ,Diseases of the respiratory system ,Sex Factors ,Internal medicine ,Humans ,Aged ,RC705-779 ,business.industry ,Oxygen Inhalation Therapy ,medicine.disease ,United States ,Cross-Sectional Studies ,Logistic Models ,030228 respiratory system ,business ,Tomography, X-Ray Computed - Abstract
Background Secondary polycythemia is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, the prevalence of polycythemia in COPD and the contributing risk factors for polycythemia in COPD have not been extensively studied. Methods We analyzed the presence of secondary polycythemia in current and former smokers with moderate to very severe COPD at the five-year follow-up visit in the observational COPDGene study. We used logistic regression to evaluate the association of polycythemia with age, sex, race, altitude, current smoking status, spirometry, diffusing capacity for carbon monoxide (DLCO), quantitative chest CT measurements (including emphysema, airway wall thickness, and pulmonary artery to aorta diameter ratio), resting hypoxemia, exercise-induced hypoxemia, and long-term oxygen therapy. Results In a total of 1928 COPDGene participants with moderate to very severe COPD, secondary polycythemia was found in 97 (9.2%) male and 31 (3.5%) female participants. In a multivariable logistic model, severe resting hypoxemia (OR 3.50, 95% CI 1.41–8.66), impaired DLCO (OR 1.28 for each 10-percent decrease in DLCO % predicted, CI 1.09–1.49), male sex (OR 3.60, CI 2.20–5.90), non-Hispanic white race (OR 3.33, CI 1.71–6.50), current smoking (OR 2.55, CI 1.49–4.38), and enrollment in the Denver clinical center (OR 4.42, CI 2.38–8.21) were associated with higher risk for polycythemia. In addition, continuous (OR 0.13, CI 0.05–0.35) and nocturnal (OR 0.46, CI 0.21–0.97) supplemental oxygen were associated with lower risk for polycythemia. Results were similar after excluding participants with anemia and participants enrolled at the Denver clinical center. Conclusions In a large cohort of individuals with moderate to very severe COPD, male sex, current smoking, enrollment at the Denver clinical center, impaired DLCO, and severe hypoxemia were associated with increased risk for secondary polycythemia. Continuous or nocturnal supplemental oxygen use were associated with decreased risk for polycythemia.
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- 2021
74. Chromatin Landscapes of Human Lung Cells Predict Potentially Functional Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Variants
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Xiaobo Zhou, Scott H. Randell, Fei Du, Feng Guo, Edwin K. Silverman, Christopher J. Benway, Michael H. Cho, and Jiangyuan Liu
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Male ,Pulmonary and Respiratory Medicine ,Clinical Biochemistry ,Pulmonary disease ,Genome-wide association study ,Computational biology ,Biology ,Response Elements ,Cell Line ,Human lung ,Pulmonary Disease, Chronic Obstructive ,medicine ,Humans ,Lung ,Molecular Biology ,Genetic association ,COPD ,Editorials ,Cell Biology ,medicine.disease ,Chromatin ,medicine.anatomical_structure ,Genetic Loci ,Female ,Functional genomics ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWASs) have identified dozens of loci associated with risk of chronic obstructive pulmonary disease (COPD). However, identifying the causal variants and their functional role in the appropriate cell type remains a major challenge. We aimed to identify putative causal variants in 82 GWAS loci associated with COPD susceptibility and predict the regulatory impact of these variants in lung-cell types. We used an integrated approach featuring statistical fine mapping, open chromatin profiling, and machine learning to identify functional variants. We generated chromatin accessibility data using the Assay for Transposase-Accessible Chromatin with High-Throughput Sequencing (ATAC-seq) for human primary lung-cell types implicated in COPD pathobiology. We then evaluated the enrichment of COPD risk variants in lung-specific open chromatin regions and generated cell type-specific regulatory predictions for6,500 variants corresponding to 82 COPD GWAS loci. Integration of the fine-mapped variants with lung open chromatin regions helped prioritize 22 variants in putative regulatory elements with potential functional effects. Comparison with functional predictions from 222 Encyclopedia of DNA Elements (ENCODE) cell samples revealed cell type-specific regulatory effects of COPD variants in the lung epithelium, endothelium, and immune cells. We identified potential causal variants for COPD risk by integrating fine mapping in GWAS loci with cell-specific regulatory profiling, highlighting the importance of leveraging the chromatin status in relevant cell types to predict the molecular effects of risk variants in lung disease.
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- 2021
75. Genome‐wide association analysis of COVID‐19 mortality risk in SARS‐CoV‐2 genomes identifies mutation in the SARS‐CoV‐2 spike protein that colocalizes with P.1 of the Brazilian strain
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Behzad Etemad, Dandi Qiao, Sharon M. Lutz, Rudolph E. Tanzi, Nan M. Laird, Chloe M. Wu, Sanghun Lee, Edwin K. Silverman, Jonathan Z. Li, Surender Khurana, Julian Hecker, Dawn L. DeMeo, Sebastien Haneuse, Abbas Mohammadi, Michael H. Cho, Katharina Ribbeck, Christoph Lange, Adrienne G. Randolph, Manish Chandra Choudhary, Scott T. Weiss, Lindsey R. Baden, Georg Hahn, and Elmira Esmaeilzadeh
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Epidemiology ,GISAID database ,Locus (genetics) ,Genome-wide association study ,Biology ,spike protein ,Genome ,SARS‐CoV‐2 ,03 medical and health sciences ,Viral entry ,Humans ,Mutation frequency ,Phylogeny ,Research Articles ,Genetics (clinical) ,030304 developmental biology ,Genetic association ,Whole genome sequencing ,Genetics ,0303 health sciences ,SARS-CoV-2 ,logistic regression ,030305 genetics & heredity ,COVID-19 ,mortality ,Mutation ,Spike Glycoprotein, Coronavirus ,Mutation (genetic algorithm) ,whole‐genome sequencing ,Brazil ,Genome-Wide Association Study ,Research Article - Abstract
SARS‐CoV‐2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS‐CoV‐2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome‐wide association studies (GWAS), we looked at the association between whole‐genome sequencing (WGS) data of the virus and COVID‐19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single‐stranded SARS‐CoV‐2 genomes of COVID‐19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome‐wide significance (p values of 4.09e−09 and 4.41e−23, respectively), though only 25,088 bp remained significant in follow‐up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e−13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow‐up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS‐CoV‐2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real‐time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.
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- 2021
76. Interstitial lung abnormalities are associated with decreased mean telomere length
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Rachel K. Putman, Gisli Thor Axelsson, Samuel Y. Ash, Jason L. Sanders, Aravind A. Menon, Tetsuro Araki, Mizuki Nishino, Masahiro Yanagawa, Elías F. Gudmundsson, Dandi Qiao, Raúl San José Estépar, Josée Dupuis, George T. O'Connor, Ivan O. Rosas, George R. Washko, Souheil El-Chemaly, Benjamin A. Raby, Vilmundur Gudnason, Dawn L. DeMeo, Edwin K. Silverman, Hiroto Hatabu, Immaculata DeVivo, Michael H. Cho, Gunnar Gudmundsson, and Gary M. Hunninghake
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Pulmonary and Respiratory Medicine ,Pulmonary Disease, Chronic Obstructive ,Humans ,Telomere ,Lung Diseases, Interstitial ,Tomography, X-Ray Computed ,Lung ,Article - Abstract
BackgroundInterstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL).MethodsTelomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality.ResultsIn all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5–3.4, p=0.0001, and OR 2.6, 95% CI 1.4–4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (−767 bp, 95% CI 76–1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1–1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4–1.7, p=0.6, and HR 1.2, 95% CI 0.6–2.2, p=0.5, respectively).ConclusionILA are associated with decreased MTL.
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- 2022
77. CRISPR interference interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells
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Rhiannon B. Werder, Tao Liu, Kristine M. Abo, Jonathan Lindstrom-Vautrin, Carlos Villacorta-Martin, Jessie Huang, Anne Hinds, Nathan Boyer, Esther Bullitt, Marc Liesa, Edwin K. Silverman, Darrell N. Kotton, Michael H. Cho, Xiaobo Zhou, Andrew A. Wilson, National Health and Medical Research Council (Australia), and National Institutes of Health (US)
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Pulmonary Disease, Chronic Obstructive ,Multidisciplinary ,Desmoplakins ,Alveolar Epithelial Cells ,Induced Pluripotent Stem Cells ,Humans ,Clustered Regularly Interspaced Short Palindromic Repeats ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWAS) have identified dozens of loci associated with chronic obstructive pulmonary disease (COPD) susceptibility; however, the function of associated genes in the cell type(s) affected in disease remains poorly understood, partly due to a lack of cell models that recapitulate human alveolar biology. Here, we apply CRISPR interference to interrogate the function of nine genes implicated in COPD by GWAS in induced pluripotent stem cell–derived type 2 alveolar epithelial cells (iAT2s). We find that multiple genes implicated by GWAS affect iAT2 function, including differentiation potential, maturation, and/or proliferation. Detailed characterization of the GWAS gene DSP demonstrates that it regulates iAT2 cell-cell junctions, proliferation, mitochondrial function, and response to cigarette smoke–induced injury. Our approach thus elucidates the biological function, as well as disease-relevant consequences of dysfunction, of genes implicated in COPD by GWAS in type 2 alveolar epithelial cells., This work was supported by a CJ Martin Early Career Fellowship from the Australian National Health and Medical Research Council awarded to R.B.W.; NIH grant F30HL147426 awarded to K.M.A.; NIH grants U01TR001810, R01DK101501, and R01DK117940 awarded to A.A.W.; NIH grants R01HL135142, R01HL137927, and R01HL147148 awarded to M.H.C.; and NIH grants R01HL127200 and R01HL148667 awarded to X.Z.
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- 2022
78. Identifying Chronic Obstructive Pulmonary Disease from Integrative Omics and Clustering in Lung Tissue
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Brian D Hobbs, Jarrett D Morrow, Xu-Wen Wang, Yang-Yu Liu, Dawn L DeMeo, Craig P Hersh, Bartolome R Celli, Raphael Bueno, Gerard J Criner, Edwin K Silverman, and Michael H Cho
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Pulmonary and Respiratory Medicine - Abstract
Background Chronic obstructive pulmonary disease (COPD) is a highly morbid and heterogenous disease. While COPD is defined by spirometry, many COPD characteristics are seen in cigarette smokers with normal spirometry. The extent to which COPD and COPD heterogeneity is captured in omics of lung tissue is not known. Methods We clustered gene expression and methylation data in 78 lung tissue samples from former smokers with normal lung function or severe COPD. We applied two integrative omics clustering methods: (1) Similarity Network Fusion (SNF) and (2) Entropy-Based Consensus Clustering (ECC). Results SNF clusters were not significantly different by the percentage of COPD cases (48.8% vs. 68.6%, p = 0.13), though were different according to median forced expiratory volume in one second (FEV1) % predicted (82 vs. 31, p = 0.017). In contrast, the ECC clusters showed stronger evidence of separation by COPD case status (48.2% vs. 81.8%, p = 0.013) and similar stratification by median FEV1% predicted (82 vs. 30.5, p = 0.0059). ECC clusters using both gene expression and methylation were identical to the ECC clustering solution generated using methylation data alone. Both methods selected clusters with differentially expressed transcripts enriched for interleukin signaling and immunoregulatory interactions between lymphoid and non-lymphoid cells. Conclusions Unsupervised clustering analysis from integrated gene expression and methylation data in lung tissue resulted in clusters with modest concordance with COPD, though were enriched in pathways potentially contributing to COPD-related pathology and heterogeneity.
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- 2022
79. NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification
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Ankit A. Desai, Wei Sun, Micheala A. Aldred, Christopher J. Rhodes, Evan L. Brittain, Stephen Y. Chan, Kathryn T. Hall, Mark W. Geraci, William M. Oldham, Andrew J. Sweatt, Jane A. Leopold, Joshua P. Fessel, Susan Dina Ghiassian, Feixiong Cheng, John Barnard, Joseph Loscalzo, Martin R. Wilkins, Neil R. Aggarwal, Rebecca Vanderpool, Lei Xiao, William C. Nichols, Anna R. Hemnes, Evelyn M. Horn, Brian D. Modena, Sara Lindström, Roham T. Zamanian, Mohit Jain, Michael H. Cho, Joe G.N. Garcia, Rachel S. Kelly, and Beth Wilmot
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medicine.medical_specialty ,Lung ,business.industry ,Vascular disease ,030204 cardiovascular system & hematology ,Precision medicine ,medicine.disease ,Omics ,Medical research ,Pulmonary hypertension ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Drug development ,medicine ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business - Abstract
The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.
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- 2021
80. Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease
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Thuonghien V. Tran, Gregory L. Kinney, Alejandro Comellas, Karin F. Hoth, Arianne K. Baldomero, A. James Mamary, Jeffrey L. Curtis, Nicola Hanania, Richard Casaburi, Kendra A. Young, Victor Kim, Barry Make, Emily S. Wan, Alejandro A. Diaz, John Hokanson, James D. Crapo, Edwin K. Silverman, Surya P. Bhatt, Elizabeth Regan, Spyridon Fortis, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Peter J. Castaldi, Michael H. Cho, Dawn L. DeMeo, Adel El Boueiz, Marilyn G. Foreman, Auyon Ghosh, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Matthew Moll, Jarrett Morrow, Dandi Qiao, Aabida Saferali, Phuwanat Sakornsakolpat, Jeong Yun, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Erin Austin, Gregory Kinney, Jessica Bon, Susan Murray, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush BanaeiKashani, Perry G. Pernicano, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D'Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D'Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh
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Pulmonary and Respiratory Medicine - Published
- 2023
81. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program
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Nancy L. Heard-Costa, Lucas Barwick, Clary B. Clish, Celeste Eng, Joanne M. Murabito, Esteban G. Burchard, Yii-Der Ida Chen, Daniel I. Chasman, Robert C. Kaplan, James B. Meigs, Deborah A. Nickerson, Cashell E. Jaquish, Eric Boerwinkle, Jennifer A. Brody, Charles Kooperberg, Mark T. Gladwin, Sebastian Schoenherr, Keng-Han Lin, John Barnard, Ryan D. Hernandez, Andrew D. Johnson, Edwin K. Silverman, Mollie A. Minear, Michelle Daya, Barbara A. Konkle, Sharon R. Browning, Daniel E. Weeks, Wendy S. Post, Alexander P. Reiner, Kathryn L. Lunetta, Gina M. Peloso, David Van Den Berg, Dan E. Arking, Seung-been Lee, Leslie A. Lange, Cristen J. Willer, Zachary A. Szpiech, Tasha E. Fingerlin, Wayne E. Clarke, Xutong Zhao, Stephen S. Rich, Nora Franceschini, Sudha Seshadri, Chloé Sarnowski, Hyun Min Kang, Sayantan Das, Michael C. Zody, Stephanie M. Fullerton, Dean Bobo, Alanna C. Morrison, Brian Custer, Nona Sotoodehnia, Shannon Kelly, Thomas W. Blackwell, Bruce M. Psaty, Yingze Zhang, Susan R. Heckbert, Robert E. Gerszten, M. Benjamin Shoemaker, Daniel Taliun, Leslie S. Emery, André Corvelo, Michael H. Cho, Braxton D. Mitchell, Xiaoming Liu, Stella Aslibekyan, Paul L. Auer, Brandon Chalazan, Sarah C. Nelson, Seung Hoan Choi, Jeong-Sun Seo, Matthew P. Conomos, Anne-Katrin Emde, Lawrence F. Bielak, Alisa K. Manning, Allison E. Ashley-Koch, Diane Fatkin, Xiaowen Tian, Emelia J. Benjamin, D. C. Rao, Mina K. Chung, Myriam Fornage, Daniel Levy, Michael D. Kessler, Weihong Tang, Daniel J. Gottlieb, Pradeep Natarajan, Jessica Lasky-Su, Amol C. Shetty, Cathy C. Laurie, Dan M. Roden, Timothy D. O’Connor, Jedidiah Carlson, Lewis C. Becker, Achilleas N. Pitsillides, Karine A. Viaud-Martinez, Raul Torres, Adolfo Correa, Christian Fuchsberger, Deborah A. Meyers, Alvaro Alonso, Sanghamitra Mohanty, Jonathon LeFaive, Soren Germer, Julie L. Mikulla, François Aguet, Susan K. Dutcher, Sarah A Gagliano Taliun, Ani Manichaikul, Lori Garman, Xiuqing Guo, Timothy A. Thornton, David D. McManus, Albert V. Smith, Kristin G. Ardlie, Anna Köttgen, Sharon L.R. Kardia, Quenna Wong, Jill M. Johnsen, Andrea Natale, Richard A. Gibbs, Douglas P. Kiel, Ingo Ruczinski, Susan Redline, Lukas Forer, Scott I. Vrieze, May E. Montasser, Rasika A. Mathias, Jerome I. Rotter, Jacob Pleiness, Chunyu Liu, Brian L. Browning, James G. Wilson, Weiniu Gan, Christine M. Albert, Marilyn J. Telen, Courtney G. Montgomery, Steven A. Lubitz, Robert Klemmer, Ramachandran S. Vasan, Nathan Pankratz, Mariza de Andrade, Vivien A. Sheehan, Kenneth Rice, Xihong Lin, Eimear E. Kenny, Stephanie M. Gogarten, John Blangero, Donna K. Arnett, Jiang He, Pankaj Qasba, James F. Casella, Patrick T. Ellinor, Nicholette D. Palmer, R. Graham Barr, Scott T. Weiss, Joanne E. Curran, Bruce S. Weir, Kari E. North, L. Adrienne Cupples, Dawn L. DeMeo, Tanika N. Kelly, Angel C.Y. Mak, Russell P. Tracy, David A. Schwartz, Kent D. Taylor, Rebecca L. Beer, Daniel N. Harris, George J. Papanicolaou, Marguerite R. Irvin, Stephen T. McGarvey, Sebastian Zöllner, Patricia A. Peyser, Brian E. Cade, Ruth J. F. Loos, Douglas Loesch, Nicholas L. Smith, Gonçalo R. Abecasis, Jennifer A. Smith, Michael E. Hall, Lu-Chen Weng, Jeffrey R. O'Connell, Adrienne M. Stilp, Donald W. Bowden, Kathleen C. Barnes, Stacey Gabriel, Michael Boehnke, Wayne Huey-Herng Sheu, and Dawood Darbar
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Quality Control ,Heterozygote ,Genomics ,Computational biology ,Biology ,Polymorphism, Single Nucleotide ,Genome ,Article ,DNA sequencing ,INDEL Mutation ,Loss of Function Mutation ,Genetics research ,Genetic variation ,Humans ,Precision Medicine ,Genetic association ,Population Density ,Multidisciplinary ,Whole Genome Sequencing ,Genome, Human ,Genetic Variation ,Rare variants ,United States ,Genetic architecture ,Phenotype ,Cytochrome P-450 CYP2D6 ,Haplotypes ,Mutagenesis ,Sample Size ,Next-generation sequencing ,National Heart, Lung, and Blood Institute (U.S.) ,Imputation (genetics) ,Reference genome - Abstract
The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%., The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.
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- 2021
82. A unifying framework for rare variant association testing in family-based designs, including higher criticism approaches, SKATs, and burden tests
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Nan M. Laird, Jessica Lasky-Su, Cecelia A. Laurie, Julian Hecker, F. William Townes, Scott T. Weiss, Priyadarshini Kachroo, Michael H. Cho, John Ziniti, and Christoph Lange
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Statistics and Probability ,0303 health sciences ,Computer science ,Cauchy distribution ,Population stratification ,computer.software_genre ,Original Papers ,01 natural sciences ,Biochemistry ,Computer Science Applications ,010104 statistics & probability ,03 medical and health sciences ,Computational Mathematics ,Computational Theory and Mathematics ,Test statistic ,Data mining ,0101 mathematics ,Null hypothesis ,Molecular Biology ,computer ,Statistic ,Sufficient statistic ,030304 developmental biology ,Statistical hypothesis testing - Abstract
Motivation Analysis of rare variants in family-based studies remains a challenge. Transmission-based approaches provide robustness against population stratification, but the evaluation of the significance of test statistics based on asymptotic theory can be imprecise. Also, power will depend heavily on the choice of the test statistic and on the underlying genetic architecture of the locus, which will be generally unknown. Results In our proposed framework, we utilize the FBAT haplotype algorithm to obtain the conditional offspring genotype distribution under the null hypothesis given the sufficient statistic. Based on this conditional offspring genotype distribution, the significance of virtually any association test statistic can be evaluated based on simulations or exact computations, without the need for asymptotic approximations. Besides standard linear burden-type statistics, this enables our approach to also evaluate other test statistics such as variance components statistics, higher criticism approaches, and maximum-single-variant-statistics, where asymptotic theory might be involved or does not provide accurate approximations for rare variant data. Based on these P-values, combined test statistics such as the aggregated Cauchy association test (ACAT) can also be utilized. In simulation studies, we show that our framework outperforms existing approaches for family-based studies in several scenarios. We also applied our methodology to a TOPMed whole-genome sequencing dataset with 897 asthmatic trios from Costa Rica. Availability and implementation FBAT software is available at https://sites.google.com/view/fbatwebpage. Simulation code is available at https://github.com/julianhecker/FBAT_rare_variant_test_simulations. Whole-genome sequencing data for ‘NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica’ is available at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000988.v4.p1. Supplementary information Supplementary data are available at Bioinformatics online.
- Published
- 2020
83. Plasma Metabolomic Signatures of Chronic Obstructive Pulmonary Disease and the Impact of Genetic Variants on Phenotype-Driven Modules
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Christine H. Wendt, Victor E. Ortega, Lucas A. Gillenwater, Yonghua Zhuang, Karan Uppal, Katherine A. Pratte, Gregory Michelotti, Russell P. Bowler, Wassim W. Labaki, Nichole Reisdorph, Michael H. Cho, Dean P. Jones, Wanda K. O'Neal, Katerina Kechris, Irina Petrache, Eitan Halper-Stromberg, Sean Jacobson, Charmion Cruickshank-Quinn, and Brian D. Hobbs
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Vital capacity ,Chronic bronchitis ,COPD ,Exacerbation ,Metabolite ,Biology ,medicine.disease ,Phenotype ,metabolomics ,metabolomic quantitative trait analysis ,integrated omics ,respiratory tract diseases ,chronic obstructive pulmonary disease ,FEV1/FVC ratio ,chemistry.chemical_compound ,Metabolomics ,chemistry ,Immunology ,medicine ,network analysis ,Original Research - Abstract
Background: Small studies have recently suggested that there are specific plasma metabolic signatures in chronic obstructive pulmonary disease (COPD), but there have been no large comprehensive study of metabolomic signatures in COPD that also integrate genetic variants. Materials and Methods: Fresh frozen plasma from 957 non-Hispanic white subjects in COPDGene was used to quantify 995 metabolites with Metabolon's global metabolomics platform. Metabolite associations with five COPD phenotypes (chronic bronchitis, exacerbation frequency, percent emphysema, post-bronchodilator forced expiratory volume at one second [FEV1]/forced vital capacity [FVC], and FEV1 percent predicted) were assessed. A metabolome-wide association study was performed to find genetic associations with metabolite levels. Significantly associated single-nucleotide polymorphisms were tested for replication with independent metabolomic platforms and independent cohorts. COPD phenotype-driven modules were identified in network analysis integrated with genetic associations to assess gene-metabolite-phenotype interactions. Results: Of metabolites tested, 147 (14.8%) were significantly associated with at least 1 COPD phenotype. Associations with airflow obstruction were enriched for diacylglycerols and branched chain amino acids. Genetic associations were observed with 109 (11%) metabolites, 72 (66%) of which replicated in an independent cohort. For 20 metabolites, more than 20% of variance was explained by genetics. A sparse network of COPD phenotype-driven modules was identified, often containing metabolites missed in previous testing. Of the 26 COPD phenotype-driven modules, 6 contained metabolites with significant met-QTLs, although little module variance was explained by genetics. Conclusion: A dysregulation of systemic metabolism was predominantly found in COPD phenotypes characterized by airflow obstruction, where we identified robust heritable effects on individual metabolite abundances. However, network analysis, which increased the statistical power to detect associations missed previously in classic regression analyses, revealed that the genetic influence on COPD phenotype-driven metabolomic modules was modest when compared with clinical and environmental factors.
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- 2020
84. Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease
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Nick Shrine, Abril G Izquierdo, Jing Chen, Richard Packer, Robert J Hall, Anna L Guyatt, Chiara Batini, Rebecca J Thompson, Chandan Pavuluri, Vidhi Malik, Brian D Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y Millwood, Zhengming Chen, Liming Li, Sara RA Wielscher, Lies Lahousse, Guy Brusselle, Andre G Uitterlinden, Ani Manichaikul, Elizabeth C Oelsner, Stephen S Rich, R. Graham Barr, Shona M Kerr, Veronique Vitart, Michael R Brown, Matthias Wielscher, Medea Imboden, Ayoung Jeong, Traci M Bartz, Sina A Gharib, Claudia Flexeder, Stefan Karrasch, Christian Gieger, Annette Peters, Beate Stubbe, Xiaowei Hu, Victor E Ortega, Deborah A Meyers, Eugene R Bleecker, Stacey B Gabriel, Namrata Gupta, Albert Vernon Smith, Jian’an Luan, Jing-Hua Zhao, Ailin F Hansen, Arnulf Langhammer, Cristen Willer, Laxmi Bhatta, David Porteous, Blair H Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George T O’Connor, Gaurav Thareja, Omar M E., Hamdi Mbarek, Karsten Suhre, Raquel Granell, Tariq O Faquih, Pieter S Hiemstra, Annelies M Slats, Benjamin H Mullin, Jennie Hui, Alan James, John Beilby, Karina Patasova, Pirro Hysi, Jukka T Koskela, Annah B Wyss, Jianping Jin, Sinjini Sikdar, Mikyeong Lee, Sebastian May-Wilson, Nicola Pirastu, Katherine A Kentistou, Peter K Joshi, Paul RHJ Timmers, Alexander T Williams, Robert C Free, Xueyang Wang, John L Morrison, Frank D Gilliland, Zhanghua Chen, Carol A Wang, Rachel E Foong, Sarah E Harris, Adele Taylor, Paul Redmond, James P Cook, Anubha Mahajan, Lars Lind, Teemu Palviainen, Terho Lehtimäki, Olli T Raitakari, Jaakko Kaprio, Taina Rantanen, Kirsi H Pietiläinen, Simon R Cox, Craig E Pennell, Graham L Hall, W. James Gauderman, Chris Brightling, James F Wilson, Tuula Vasankari, Tarja Laitinen, Veikko Salomaa, Dennis O Mook-Kanamori, Nicholas J Timpson, Eleftheria Zeggini, Josée Dupuis, Caroline Hayward, Ben Brumpton, Claudia Langenberg, Stefan Weiss, Georg Homuth, Carsten Oliver Schmidt, Nicole Probst-Hensch, Marjo-Riitta Jarvelin, Alanna C Morrison, Ozren Polasek, Igor Rudan, Joo-Hyeon Lee, Ian Sayers, Emma L Rawlins, Frank Dudbridge, Edwin K Silverman, David P Strachan, Robin G Walters, Andrew P Morris, Stephanie J London, Michael H Cho, Louise V Wain, Ian P Hall, and Martin D Tobin
- Abstract
Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
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- 2022
85. Genetic Associations and Architecture of Asthma-COPD Overlap
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Catherine John, Anna L. Guyatt, Nick Shrine, Richard Packer, Thorunn A. Olafsdottir, Jiangyuan Liu, Lystra P. Hayden, Su H. Chu, Jukka T. Koskela, Jian’an Luan, Xingnan Li, Natalie Terzikhan, Hanfei Xu, Traci M. Bartz, Hans Petersen, Shuguang Leng, Steven A. Belinsky, Aivaras Cepelis, Ana I. Hernández Cordero, Ma’en Obeidat, Gudmar Thorleifsson, Deborah A. Meyers, Eugene R. Bleecker, Lori C. Sakoda, Carlos Iribarren, Yohannes Tesfaigzi, Sina A. Gharib, Josée Dupuis, Guy Brusselle, Lies Lahousse, Victor E. Ortega, Ingileif Jonsdottir, Don D. Sin, Yohan Bossé, Maarten van den Berge, David Nickle, Jennifer K. Quint, Ian Sayers, Ian P. Hall, Claudia Langenberg, Samuli Ripatti, Tarja Laitinen, Ann C. Wu, Jessica Lasky-Su, Per Bakke, Amund Gulsvik, Craig P. Hersh, Caroline Hayward, Arnulf Langhammer, Ben Brumpton, Kari Stefansson, Michael H. Cho, Louise V. Wain, Martin D. Tobin, University of Helsinki, Institute for Molecular Medicine Finland, Faculty Common Matters (Faculty of Social Sciences), Department of Public Health, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Groningen Research Institute for Asthma and COPD (GRIAC), and Epidemiology
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Pulmonary and Respiratory Medicine ,HAY-FEVER ,Pulmonary Disease, Chronic Obstructive/complications ,Smoking/genetics ,Respiratory System ,spirometry ,LOCI ,Asthma/diagnosis ,Critical Care and Intensive Care Medicine ,OBSTRUCTIVE PULMONARY-DISEASE ,Pulmonary Disease, Chronic Obstructive ,BLOOD EOSINOPHIL COUNT ,immune system diseases ,Humans ,COPD ,GENOME-WIDE ASSOCIATION ,Lung ,RISK ,genome-wide association study ,HERITABILITY ,Smoking ,1103 Clinical Sciences ,asthma ,3126 Surgery, anesthesiology, intensive care, radiology ,respiratory tract diseases ,EXACERBATIONS ,3121 General medicine, internal medicine and other clinical medicine ,epidemiology ,Cardiology and Cardiovascular Medicine ,Genome-Wide Association Study - Abstract
Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.
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- 2022
86. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
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Tetsushi, Nakao, Alexander G, Bick, Margaret A, Taub, Seyedeh M, Zekavat, Md M, Uddin, Abhishek, Niroula, Cara L, Carty, John, Lane, Michael C, Honigberg, Joshua S, Weinstock, Akhil, Pampana, Christopher J, Gibson, Gabriel K, Griffin, Shoa L, Clarke, Romit, Bhattacharya, Themistocles L, Assimes, Leslie S, Emery, Adrienne M, Stilp, Quenna, Wong, Jai, Broome, Cecelia A, Laurie, Alyna T, Khan, Albert V, Smith, Thomas W, Blackwell, Veryan, Codd, Christopher P, Nelson, Zachary T, Yoneda, Juan M, Peralta, Donald W, Bowden, Marguerite R, Irvin, Meher, Boorgula, Wei, Zhao, Lisa R, Yanek, Kerri L, Wiggins, James E, Hixson, C Charles, Gu, Gina M, Peloso, Dan M, Roden, Muagututi'a S, Reupena, Chii-Min, Hwu, Dawn L, DeMeo, Kari E, North, Shannon, Kelly, Solomon K, Musani, Joshua C, Bis, Donald M, Lloyd-Jones, Jill M, Johnsen, Michael, Preuss, Russell P, Tracy, Patricia A, Peyser, Dandi, Qiao, Pinkal, Desai, Joanne E, Curran, Barry I, Freedman, Hemant K, Tiwari, Sameer, Chavan, Jennifer A, Smith, Nicholas L, Smith, Tanika N, Kelly, Bertha, Hidalgo, L Adrienne, Cupples, Daniel E, Weeks, Nicola L, Hawley, Ryan L, Minster, Ranjan, Deka, Take T, Naseri, Lisa, de Las Fuentes, Laura M, Raffield, Alanna C, Morrison, Paul S, Vries, Christie M, Ballantyne, Eimear E, Kenny, Stephen S, Rich, Eric A, Whitsel, Michael H, Cho, M Benjamin, Shoemaker, Betty S, Pace, John, Blangero, Nicholette D, Palmer, Braxton D, Mitchell, Alan R, Shuldiner, Kathleen C, Barnes, Susan, Redline, Sharon L R, Kardia, Gonçalo R, Abecasis, Lewis C, Becker, Susan R, Heckbert, Jiang, He, Wendy, Post, Donna K, Arnett, Ramachandran S, Vasan, Dawood, Darbar, Scott T, Weiss, Stephen T, McGarvey, Mariza, de Andrade, Yii-Der Ida, Chen, Robert C, Kaplan, Deborah A, Meyers, Brian S, Custer, Adolfo, Correa, Bruce M, Psaty, Myriam, Fornage, JoAnn E, Manson, Eric, Boerwinkle, Barbara A, Konkle, Ruth J F, Loos, Jerome I, Rotter, Edwin K, Silverman, Charles, Kooperberg, John, Danesh, Nilesh J, Samani, Siddhartha, Jaiswal, Peter, Libby, Patrick T, Ellinor, Nathan, Pankratz, Benjamin L, Ebert, Alexander P, Reiner, Rasika A, Mathias, Ron, Do, and Pradeep, Natarajan
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Multidisciplinary - Abstract
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
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- 2022
87. Associations of the MUC5B promoter variant with timing of interstitial lung disease and rheumatoid arthritis onset
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Gregory McDermott, Ritu Gill, Staci Gagne, Suzanne Byrne, Weixing Huang, Jing Cui, Lauren Prisco, Alessandra Zaccardelli, Lily Martin, Vanessa L Kronzer, Matthew Moll, Michael H Cho, Nancy Shadick, Paul F Dellaripa, Tracy Doyle, and Jeffrey A Sparks
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Male ,Middle Aged ,Mucin-5B ,Arthritis, Rheumatoid ,Logistic Models ,Rheumatology ,Basic Science ,Odds Ratio ,Disease Progression ,Humans ,Pharmacology (medical) ,Female ,Lung Diseases, Interstitial ,Promoter Regions, Genetic - Abstract
Objectives To investigate the associations of the common MUC5B promoter variant with timing of RA-associated interstitial lung disease (RA-ILD) and RA onset. Methods We identified patients with RA meeting 2010 ACR/EULAR criteria and available genotype information in the Mass General Brigham Biobank, a multihospital biospecimen and clinical data collection research study. We determined RA-ILD presence by reviewing all RA patients who had CT imaging, lung biopsy or autopsy results. We determined the dates of RA and RA-ILD diagnoses by manual records review. We examined the associations of the MUC5B promoter variant (G>T at rs35705950) with RA-ILD, RA-ILD occurring before or within 2 years of RA diagnosis and RA diagnosis at age >55 years. We used multivariable logistic regression to estimate odds ratios (ORs) for each outcome by MUC5B promoter variant status, adjusting for potential confounders including genetic ancestry and smoking. Results We identified 1005 RA patients with available genotype data for rs35705950 (mean age 45 years, 79% female, 81% European ancestry). The MUC5B promoter variant was present in 155 (15.4%) and was associated with RA-ILD [multivariable OR 3.34 (95% CI 1.97, 5.60)], RA-ILD before or within 2 years of RA diagnosis [OR 4.01 (95% CI 1.78, 8.80)] and RA onset after age 55 years [OR 1.52 (95% CI 1.08, 2.12)]. Conclusions The common MUC5B promoter variant was associated with RA-ILD onset earlier in the RA disease course and older age of RA onset. These findings suggest that the MUC5B promoter variant may impact RA-ILD risk early in the RA disease course, particularly in patients with older-onset RA.
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- 2022
88. Genome-Wide Gene-by-Smoking Interaction Study of Chronic Obstructive Pulmonary Disease
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John E. Hokanson, Nick Shrine, Brian D. Hobbs, Dmitry Prokopenko, Carl A. Melbourne, Edwin K. Silverman, Sharon M. Lutz, Louise V. Wain, Martin D. Tobin, Woori Kim, Phuwanat Sakornsakolpat, Terri H. Beaty, and Michael H. Cho
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Male ,Oncology ,medicine.medical_specialty ,MECOM ,Epidemiology ,Genome-wide association study ,Locus (genetics) ,White People ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetic predisposition ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene–environment interaction ,Allele ,030304 developmental biology ,Genetic association ,0303 health sciences ,COPD ,business.industry ,Smoking ,Original Contribution ,Middle Aged ,medicine.disease ,United Kingdom ,Respiratory Function Tests ,030228 respiratory system ,Case-Control Studies ,Female ,Gene-Environment Interaction ,business ,Genome-Wide Association Study - Abstract
Risk of chronic obstructive pulmonary disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degrees-of-freedom (df) test) as well as interaction effects alone (1-df interaction test). We sought to replicate significant results in COPDGene (United States, 2008–2010) and SpiroMeta Consortium (multiple countries, 1947–2015) data. We considered 2 smoking variables: 1) ever/never and 2) current/noncurrent. In the 1-df test, we identified 1 genome-wide significant locus on 15q25.1 (cholinergic receptor nicotinic β4 subunit, or CHRNB4) for ever- and current smoking and identified PI*Z allele (rs28929474) of serpin family A member 1 (SERPINA1) for ever-smoking and 3q26.2 (MDS1 and EVI1 complex locus, or MECOM) for current smoking in an analysis of previously reported COPD loci. In the 2-df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (sphingomyelin phosphodiesterase 3, or SMPD3) and 19q13.2 (Egl-9 family hypoxia inducible factor 2, or EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci; however, we failed to identify novel susceptibility loci.
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- 2020
89. Statistical considerations for the analysis of massively parallel reporter assays data
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Edwin K. Silverman, Peter J. Castaldi, Michael H. Cho, Nan H. Laird, Corwin M. Zigler, Dandi Qiao, and Xiaobo Zhou
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RNA, Untranslated ,Epidemiology ,Computer science ,Gene Expression ,Computational biology ,Regulatory Sequences, Nucleic Acid ,Article ,03 medical and health sciences ,Humans ,Massively parallel ,Alleles ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,030305 genetics & heredity ,Genetic variants ,Nonparametric statistics ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,DNA ,Noncoding DNA ,Fully developed ,R package ,Research Design ,Allelic Imbalance ,Software ,Type I and type II errors - Abstract
Noncoding DNA contains gene regulatory elements that alter gene expression, and the function of these elements can be modified by genetic variation. Massively parallel reporter assays (MPRA) enable high-throughput identification and characterization of functional genetic variants, but the statistical methods to identify allelic effects in MPRA data have not been fully developed. In this study, we demonstrate how the baseline allelic imbalance in MPRA libraries can produce biased results, and we propose a novel, nonparametric, adaptive testing method that is robust to this bias. We compare the performance of this method with other commonly used methods, and we demonstrate that our novel adaptive method controls Type I error in a wide range of scenarios while maintaining excellent power. We have implemented these tests along with routines for simulating MPRA data in the Analysis Toolset for MPRA (@MPRA), an R package for the design and analyses of MPRA experiments. It is publicly available at http://github.com/redaq/atMPRA.
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- 2020
90. Machine Learning Characterization of COPD Subtypes
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Peter J. Castaldi, Adel Boueiz, Jeong Yun, Raul San Jose Estepar, James C. Ross, George Washko, Michael H. Cho, Craig P. Hersh, Gregory L. Kinney, Kendra A. Young, Elizabeth A. Regan, David A. Lynch, Gerald J. Criner, Jennifer G. Dy, Stephen I. Rennard, Richard Casaburi, Barry J. Make, James Crapo, Edwin K. Silverman, John E. Hokanson, James D. Crapo, Terri Beaty, Ferdouse Begum, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Jacqueline Hetmanski, Brian D. Hobbs, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, and Farnoush Banaei-Kashani
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Pulmonary and Respiratory Medicine ,Spirometry ,COPD ,medicine.diagnostic_test ,business.industry ,Context (language use) ,Disease ,Critical Care and Intensive Care Medicine ,medicine.disease ,Machine learning ,computer.software_genre ,Subtyping ,respiratory tract diseases ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Genetic epidemiology ,medicine ,Clinical significance ,030212 general & internal medicine ,Artificial intelligence ,Genetic risk ,Cardiology and Cardiovascular Medicine ,business ,computer - Abstract
COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.
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- 2020
91. Asthma, Chronic Obstructive Pulmonary Disease, and Subsequent Risk for Incident Rheumatoid Arthritis Among Women: A Prospective Cohort Study
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Julia A. Ford, Bing Lu, Karen H. Costenbader, Michael H. Cho, Jeffrey A. Sparks, Edwin K. Silverman, Xinyi Liu, Carlos A. Camargo, and Su H. Chu
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030203 arthritis & rheumatology ,medicine.medical_specialty ,COPD ,Proportional hazards model ,business.industry ,Immunology ,Hazard ratio ,Confounding ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Internal medicine ,Rheumatoid arthritis ,medicine ,Immunology and Allergy ,030212 general & internal medicine ,Risk factor ,Prospective cohort study ,business ,Asthma - Abstract
OBJECTIVE Inflamed airways are hypothesized to contribute to rheumatoid arthritis (RA) pathogenesis due to RA-related autoantibody production, and smoking is the strongest environmental RA risk factor. However, the role of chronic airway diseases in RA development is unclear. We undertook this study to investigate whether asthma and chronic obstructive pulmonary disease (COPD) were each associated with RA. METHODS We performed a prospective cohort study of 205,153 women in the Nurses' Health Study (NHS, 1988-2014) and NHSII (1991-2015). Exposures were self-reported physician-diagnosed asthma or COPD confirmed by validated supplemental questionnaires. The primary outcome was incident RA confirmed by medical record review by 2 rheumatologists. Covariates (including smoking pack-years/status) were assessed via biennial questionnaires. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for RA were estimated using Cox regression. RESULTS We identified 15,148 women with confirmed asthma, 3,573 women with confirmed COPD, and 1,060 incident RA cases during 4,384,471 person-years (median 24.0 years/participant) of follow-up in the NHS and NHSII. Asthma was associated with increased RA risk (HR 1.53 [95% CI 1.24-1.88]) compared to no asthma/COPD after adjustment for covariates, including smoking pack-years/status. Asthma remained associated with increased RA risk when analyzing only never-smokers (HR 1.53 [95% CI 1.14-2.05]). COPD was also associated with increased RA risk (HR 1.89 [95% CI 1.31-2.75]). The association of COPD with RA was most pronounced in the subgroup of ever-smokers age >55 years (HR 2.20 [95% CI 1.38-3.51]). CONCLUSION Asthma and COPD were each associated with increased risk of incident RA, independent of smoking status/intensity and other potential confounders. These results provide support for the hypothesis that chronic airway inflammation may be crucial in RA pathogenesis.
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- 2020
92. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts
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Alison D. Murray, Anna L. Guyatt, Jing Hua Zhao, Eugene R. Bleecker, Matthias Wielscher, Frank Dudbridge, Martin D. Tobin, Veronique Vitart, Ida Surakka, Nadia N. Hansel, Ozren Polasek, Caroline Hayward, David P. Strachan, Per Bakke, Stefan Karrasch, Anubha Mahajan, James F. Wilson, Shona M. Kerr, Ruth Tal-Singer, James D. Crapo, Victoria E. Jackson, Jonathan Marten, Olli T. Raitakari, María Soler Artigas, Medea Imboden, Sungho Won, Beate Stubbe, Ulf Gyllensten, George R. Washko, Eleftheria Zeggini, David A. Lynch, Brian D. Hobbs, Matthew Moll, Mika Kähönen, Rajesh Rawal, Guy Brusselle, Ma'en Obeidat, Nicholas J. Wareham, Claudia Langenberg, Nicole Probst-Hensch, Peter K. Joshi, Blair H. Smith, Stefan Weiss, Woo Jin Kim, Kathleen C. Barnes, Sarah E. Harris, David J. Porteous, Stefan Enroth, Ian P. Hall, Alan L. James, Sina A. Gharib, Paul R. H. J. Timmers, Xingnan Li, Louise V. Wain, John E. Hokanson, Holger Schulz, Ralf Ewert, Ani Manichaikul, Lies Lahousse, Georg Homuth, R. Graham Barr, Scott T. Weiss, Phuwanat Sakornsakolpat, Sara R.A. Wijnant, Edwin K. Silverman, Christian Gieger, Jennie Hui, Andrew P. Morris, James P. Cook, Michael J. McGeachie, Dawn L. DeMeo, Nick Shrine, Traci M. Bartz, Amund Gulsvik, Deborah A. Meyers, Katherine A. Kentistou, Igor Rudan, Jian'an Luan, Ian J. Deary, Catherine John, Michael H. Cho, Lars Lind, Marjo-Riitta Järvelin, Ah Ra Do, Terho Lehtimäki, Stephen S. Rich, Bruce M. Psaty, Tampere University, Department of Clinical Physiology and Nuclear Medicine, Clinical Medicine, Department of Clinical Chemistry, Epidemiology, and Pulmonary Medicine
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Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,AMERICAN THORACIC SOCIETY ,Vital Capacity ,LOCI ,Genome-wide association study ,EMPHYSEMA ,Cohort Studies ,03 medical and health sciences ,FEV1/FVC ratio ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Forced Expiratory Volume ,adult ,case-control studies ,cohort studies ,female ,forced expiratory volume ,genome-wide association study ,humans ,male ,middle aged ,phenotype ,pulmonary disease, chronic obstructive ,risk factors ,vital capacity ,Medicine and Health Sciences ,medicine ,COPD ,Humans ,SMOKING-BEHAVIOR ,030212 general & internal medicine ,GENOME-WIDE ASSOCIATION ,FAMILIAL AGGREGATION ,GENETIC EPIDEMIOLOGY ,Framingham Risk Score ,HERITABILITY ,business.industry ,Case-control study ,Family aggregation ,Odds ratio ,Articles ,Middle Aged ,medicine.disease ,respiratory tract diseases ,LUNG-FUNCTION ,Phenotype ,030228 respiratory system ,Genetic epidemiology ,Case-Control Studies ,Female ,3111 Biomedicine ,business ,Genome-Wide Association Study - Abstract
Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1
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- 2020
93. A statistical physics approach for disease module detection
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Xu-Wen Wang, Dandi Qiao, Michael H. Cho, Dawn L. DeMeo, Edwin K. Silverman, and Yang-Yu Liu
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Physics ,Genetics ,Humans ,Protein Interaction Maps ,Genetics (clinical) ,Algorithms ,Genome-Wide Association Study - Abstract
Extensive evidence indicates that the pathobiological processes of a complex disease are associated with perturbation within specific disease neighborhoods of the human protein-protein interaction (PPI) network (a.k.a. the interactome), often referred to as the disease module. Many computational methods have been developed to integrate the interactome and omics profiles to extract context-dependent disease modules. Yet, existing methods all have fundamental limitations in terms of rigor and/or efficiency. Here, we developed a statistical physics approach based on the random-field Ising model (RFIM) for disease module detection, which is both mathematically rigorous and computationally efficient. We applied our RFIM approach with genome-wide association studies (GWAS) of six complex diseases to examine its performance for disease module detection. We found that our RFIM approach outperforms existing methods in terms of computational efficiency, connectivity of disease modules, and robustness to the interactome incompleteness.
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- 2022
94. SciViewer- An interactive browser for visualizing single cell datasets
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Dhawal Jain, Sikander Hayat, Xinkai Li, Joydeep Charkaborty, Pooja Srinivasa, Michael H. Cho, Edwin K. Silverman, Hobert Moore, Rafael Kramann, and Alexis Laux-Biehlmann
- Abstract
Single-cell sequencing improves our ability to understand biological systems at single-cell resolution and can be used to identify novel drug targets and optimal cell-types for target validation. However, tools that can interactively visualize and provide target-centric views of these large datasets are limited. We present SciViewer (Single-cell Interactive Viewer), a novel tool to interactively visualize, annotate and share single-cell datasets. SciViewer allows visualization of cluster, gene and pathway level information such as clustering annotation, differential expression, pathway enrichment, cell-type specificity, cellular composition, normalized gene expression and comparison across datasets. Further, we provide APIs for SciViewer to interact with publicly available pharmacogenomics databases for systematic evaluation of potential novel drug targets. We provide a module for non-programmatic upload of single-cell datasets. SciViewer will be a useful tool for data exploration and target discovery from single-cell datasets. It is available on GitHub (https://github.com/Dhawal-Jain/SciViewer).
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- 2022
95. Blood Gene Expression Risk Profiles and Interstitial Lung Abnormalities: COPDGene and ECLIPSE cohort studies
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Matthew Moll, Brian D. Hobbs, Aravind Menon, Auyon J. Ghosh, Rachel K. Putman, Takuya Hino, Akinori Hata, Edwin K. Silverman, John Quackenbush, Peter J. Castaldi, Craig P. Hersh, Michael J. McGeachie, Don D. Sin, Ruth Tal-Singer, Mizuki Nishino, Hiroto Hatabu, Gary M. Hunninghake, and Michael H. Cho
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Cohort Studies ,Humans ,respiratory system ,Lung Diseases, Interstitial ,Tomography, X-Ray Computed ,Transcriptome ,Lung ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases - Abstract
RationaleInterstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Blood gene expression profiles can predict IPF mortality, but whether these same genes associate with ILA and ILA outcomes is unknown.ObjectivesTo evaluate if a previously described blood gene expression profile associated with IPF mortality is associated with ILA and all-cause mortality.MethodsIn COPDGene and ECLIPSE study participants with visual scoring of ILA and gene expression data, we evaluated the association of a previously described IPF mortality score with ILA and mortality. We also trained a new ILA score, derived using genes from the IPF score, in a subset of COPDGene. We tested the association with ILA and mortality on the remainder of COPDGene and ECLIPSE.Measurements and Main ResultsIn 1,469 COPDGene (training n=734; testing n=735) and 571 ECLIPSE participants, the IPF score was not associated with ILA or mortality. However, an ILA score derived from IPF score genes was associated with ILA (meta-analysis of test datasets OR 1.4 [95% CI: 1.2-1.6]) and mortality (HR 1.25 [95% CI: 1.12-1.41]). Six of the 11 genes in the ILA score had discordant directions of effects compared to the IPF score. The ILA score partially mediated the effects of age on mortality (11.8% proportion mediated).ConclusionsAn ILA gene expression score, derived from IPF mortality-associated genes, identified genes with concordant and discordant effects on IPF mortality and ILA. These results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death.Key messagesWhat is the key questionInterstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Do blood gene expression profiles that predict IPF mortality also associate with ILA?What is the bottom lineAn ILA gene expression score, derived from IPF mortality-associated genes, was associated with ILA and all-cause mortality. This score identified genes with concordant and discordant effects on IPF mortality and ILA. Our results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death.Why read onOur results lend insight into how gene expression profiles and biological pathways associated with IPF prognosis relate to ILA and all-cause mortality
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- 2022
96. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
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Margaret A. Taub, Matthew P. Conomos, Rebecca Keener, Kruthika R. Iyer, Joshua S. Weinstock, Lisa R. Yanek, John Lane, Tyne W. Miller-Fleming, Jennifer A. Brody, Laura M. Raffield, Caitlin P. McHugh, Deepti Jain, Stephanie M. Gogarten, Cecelia A. Laurie, Ali Keramati, Marios Arvanitis, Albert V. Smith, Benjamin Heavner, Lucas Barwick, Lewis C. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Esteban G. Burchard, Juan C. Celedón, Yen Pei C. Chang, Brian Custer, Dawood Darbar, Lisa de las Fuentes, Dawn L. DeMeo, Barry I. Freedman, Melanie E. Garrett, Mark T. Gladwin, Susan R. Heckbert, Bertha A. Hidalgo, Marguerite R. Irvin, Talat Islam, W. Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E. North, Patricia A. Peyser, Nicholas Rafaels, Christine Seidman, Daniel E. Weeks, Fayun Wen, Marsha M. Wheeler, L. Keoki Williams, Ivana V. Yang, Wei Zhao, Stella Aslibekyan, Paul L. Auer, Donald W. Bowden, Brian E. Cade, Zhanghua Chen, Michael H. Cho, L. Adrienne Cupples, Joanne E. Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha E. Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M. Johnsen, Eimear E. Kenny, Albert M. Levin, Chunyu Liu, Ryan L. Minster, Take Naseri, Mehdi Nouraie, Muagututi‘a Sefuiva Reupena, Ester C. Sabino, Jennifer A. Smith, Nicholas L. Smith, Jessica Lasky-Su, James G. Taylor, Marilyn J. Telen, Hemant K. Tiwari, Russell P. Tracy, Marquitta J. White, Yingze Zhang, Kerri L. Wiggins, Scott T. Weiss, Ramachandran S. Vasan, Kent D. Taylor, Moritz F. Sinner, Edwin K. Silverman, M. Benjamin Shoemaker, Wayne H.-H. Sheu, Frank Sciurba, David A. Schwartz, Jerome I. Rotter, Daniel Roden, Susan Redline, Benjamin A. Raby, Bruce M. Psaty, Juan M. Peralta, Nicholette D. Palmer, Sergei Nekhai, Courtney G. Montgomery, Braxton D. Mitchell, Deborah A. Meyers, Stephen T. McGarvey, Angel C.Y. Mak, Ruth J.F. Loos, Rajesh Kumar, Charles Kooperberg, Barbara A. Konkle, Shannon Kelly, Sharon L.R. Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank D. Gilliland, Bruce D. Gelb, Myriam Fornage, Patrick T. Ellinor, Mariza de Andrade, Adolfo Correa, Yii-Der Ida Chen, Eric Boerwinkle, Kathleen C. Barnes, Allison E. Ashley-Koch, Donna K. Arnett, Christine Albert, Cathy C. Laurie, Goncalo Abecasis, Deborah A. Nickerson, James G. Wilson, Stephen S. Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas W. Blackwell, Timothy Thornton, Jeff O’Connell, Nancy J. Cox, James A. Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander P. Reiner, and Rasika A. Mathias
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Genetics ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Article - Abstract
Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value
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- 2022
97. Quantitative Interstitial Abnormality Progression and Outcomes in the COPDGene and PLuSS Cohorts
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Bina, Choi, Najma, Adan, Tracy J, Doyle, Ruben, San José Estépar, Rola, Harmouche, Stephen M, Humphries, Matthew, Moll, Michael H, Cho, Rachel K, Putman, Gary M, Hunninghake, Ravi, Kalhan, Gabrielle Y, Liu, Alejandro A, Diaz, Stefanie E, Mason, Farbod N, Rahaghi, Carrie L, Pistenmaa, Nicholas, Enzer, Clare, Poynton, Gonzalo Vegas, Sánchez-Ferrero, James C, Ross, David A, Lynch, Fernando J, Martinez, MeiLan K, Han, Russell P, Bowler, David O, Wilson, Ivan O, Rosas, George R, Washko, Raúl, San José Estépar, and Samuel Y, Ash
- Abstract
The risk factors and clinical outcomes of quantitative interstitial abnormality progression over time have not been characterized.What are the associations of quantitative interstitial abnormality progression with lung function, exercise capacity, and mortality? What are the demographic and genetic risk factors for quantitative interstitial abnormality progression?Quantitative interstitial abnormality progression between visits 1 and 2 was assessed from 4,635 participants in the Genetic Epidemiology of COPD (COPDGene) cohort and 1,307 participants in the Pittsburgh Lung Screening Study (PLuSS) cohort. We used multivariable linear regression to determine the risk factors for progression and the longitudinal associations between progression and FVC and 6-min walk distance, and Cox regression models for the association with mortality.Age at enrollment, female sex, current smoking status, and the MUC5B minor allele were associated with quantitative interstitial abnormality progression. Each percent annual increase in quantitative interstitial abnormalities was associated with annual declines in FVC (COPDGene: 8.5 mL/y; 95% CI, 4.7-12.4 mL/y; P .001; PLuSS: 9.5 mL/y; 95% CI, 3.7-15.4 mL/y; P = .001) and 6-min walk distance, and increased mortality (COPDGene: hazard ratio, 1.69; 95% CI, 1.34-2.12; P .001; PLuSS: hazard ratio, 1.28; 95% CI, 1.10-1.49; P = .001).The objective, longitudinal measurement of quantitative interstitial abnormalities may help identify people at greatest risk for adverse events and most likely to benefit from early intervention.
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- 2022
98. Protein prediction for trait mapping in diverse populations
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George J. Papanicolaou, Peter Durda, Ashley J. Mulford, Russell P. Tracy, Kent D. Taylor, Christopher R. Gignoux, Xiuqing Guo, Cathy C. Laurie, Ryan Schubert, Timothy A. Thornton, Matthew P. Conomos, Leslie A. Lange, Ethan M. Lange, Isabelle Gregga, W. Craig Johnson, Clary B. Clish, Hae Kyung Im, David Van Den Berg, Elaine Cornell, Yongmei Liu, Anna V. Mikhaylova, Tuuli Lappalainen, Jerome I. Rotter, François Aguet, Robert E. Gerszten, Michael H. Cho, Elyse Geoffroy, Heather E. Wheeler, Kristin G. Ardlie, Ani Manichaikul, Stephen S. Rich, Thomas W. Blackwell, and Wang, Heming
- Subjects
Male ,Proteome ,General Science & Technology ,NHLBI TOPMed Consortium ,Population ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Genome-wide association study ,Genomics ,Pilot Projects ,Human genetic variation ,Computational biology ,Biology ,Gene Frequency ,Genetic ,Models ,Genetics ,Humans ,Polymorphism ,education ,Genetic Association Studies ,Genetic association ,education.field_of_study ,Human Genome ,Proteins ,Single Nucleotide ,Atherosclerosis ,Good Health and Well Being ,Trait ,Female ,Generic health relevance ,Biotechnology - Abstract
Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n=183), Chinese (n=71), European (n=416), and Hispanic/Latino (n=301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises ~50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods athttps://doi.org/10.5281/zenodo.4837328.Author summaryGene regulation is a critical mechanism underlying complex traits. Transcriptome-wide association studies (TWAS) have helped elucidate potential mechanisms because each association connects a gene rather than a variant to the complex trait. Like genome-wide association studies (GWAS), most TWAS are still conducted exclusively in populations of European ancestry, which misses the opportunity to test the full spectrum of human genetic variation for associations with complex traits. Here, move beyond the transcriptome and because protein measurement assays are growing to allow interrogation of the proteome, we use data from TOPMed MESA to develop genetic predictors of protein abundance in diverse ancestry populations. We compare model-building strategies with the goal of providing the best resource for protein association discovery with available data. We demonstrate how these prediction models can be used to perform proteome-wide association studies (PWAS) in diverse populations. We show the most protein-trait associations were discovered, colocalized, and replicated in independent cohorts using proteome prediction model training populations with similar ancestries to individuals in the GWAS. We shared our protein prediction models and performance statistics publicly to facilitate future proteome mapping studies in diverse populations.
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- 2022
99. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma
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Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner
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Adult ,Costa Rica ,Male ,Pulmonary and Respiratory Medicine ,Adolescent ,Vital Capacity ,Single-nucleotide polymorphism ,Pedigree chart ,Critical Care and Intensive Care Medicine ,Young Adult ,03 medical and health sciences ,FEV1/FVC ratio ,0302 clinical medicine ,Polymorphism (computer science) ,Forced Expiratory Volume ,Humans ,Medicine ,SNP ,030212 general & internal medicine ,Child ,Asthma ,Whole Genome Sequencing ,business.industry ,Middle Aged ,respiratory system ,medicine.disease ,respiratory tract diseases ,Minor allele frequency ,030228 respiratory system ,Genetic epidemiology ,Child, Preschool ,Interferon Regulatory Factors ,Immunology ,Respiratory Physiological Phenomena ,Female ,Cardiology and Cardiovascular Medicine ,business ,Cell Adhesion Molecules - Abstract
BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
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- 2019
100. Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis
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Mizuki Nishino, Shwu Fan Ma, John D. Newell, Brian D. Hobbs, Purnema Madahar, Ani Manichaikul, Deborah A. Meyers, Vilmundur Gudnason, Tetsuro Araki, Gunnar Gudmundsson, Anna J. Podolanczuk, R. Graham Barr, David J. Lederer, George R. Washko, Victor E. Ortega, Justin M. Oldham, R. Gisli Jenkins, David A. Schwartz, Jerome I. Rotter, Gudny Eiriksdottir, Hanfei Xu, Stephen S. Rich, Louise V. Wain, Toby M. Maher, Imre Noth, Stephen P. Peters, Michael H. Cho, Tasha E. Fingerlin, Rachel K. Putman, Richard J. Allen, Hiroto Hatabu, Elizabeth J. Ampleford, George T. O'Connor, Wanda K. O'Neal, Josée Dupuis, Ivan O. Rosas, Gary M. Hunninghake, Nuno Rodrigues Zilhao Nogueira, Eugene R. Bleecker, Jennifer N. Nguyen, Richard Hubbard, Edwin K. Silverman, National Institute for Health Research, and British Lung Foundation
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Respiratory System ,SNP ,Genome-wide association study ,Single-nucleotide polymorphism ,Critical Care and Intensive Care Medicine ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,interstitial lung abnormalities ,Risk Factors ,Fibrosis ,Epidemiology ,medicine ,Humans ,genetics ,030212 general & internal medicine ,Respiratory system ,11 Medical and Health Sciences ,genome-wide association study ,Lung ,business.industry ,Original Articles ,single-nucleotide polymorphism ,respiratory system ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,medicine.anatomical_structure ,030228 respiratory system ,Lung Diseases, Interstitial ,business - Abstract
Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known. Objectives: To perform a genome-wide association study (GWAS) of ILAs. Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10(−27)) and subpleural ILAs (P = 1.6 × 10(−29)). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10(−8)) and FCF1P3 (rs73199442, P = 4.8 × 10(−8)) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10(−8)) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P
- Published
- 2019
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