한빛사논문
- 조회338
Mikyeong Lee 1, Tianxiao Huan 2,3, Daniel L McCartney 4, Geetha Chittoor 5,6, Maaike de Vries 7,8, Lies Lahousse 9,10, Jennifer N Nguyen 11, Jennifer A Brody 12, Juan Castillo-Fernandez 13, Natalie Terzikhan 10, Cancan Qi 8,14, Roby Joehanes 3, Josine L Min 15,16, Gordon J Smilnak 1, Jessica R Shaw 17, Chen Xi Yang 18, Elena Colicino 19, Thanh T Hoang 1, Mairead L Bermingham 4, Hanfei Xu 20, Anne E Justice 5,6, Cheng-Jian Xu 21,22,23,24, Stephen S Rich 11, Simon R Cox 25, Judith M Vonk 7,8, Ivana Prokić 10, Nona Sotoodehnia 26, Pei-Chien Tsai 13,27,28, Joel D Schwartz 29,30,31, Janice M Leung 18, Sinjini Sikdar 1,32, Rosie M Walker 4, Sarah E Harris 25, Diana A van der Plaat 7,33, David J Van Den Berg 34,35, Traci M Bartz 36, Tim D Spector 13, Pantel S Vokonas 37, Riccardo E Marioni 4, Adele M Taylor 25, Yongmei Liu 38, R Graham Barr 39,40, Leslie A Lange 17,41, Andrea A Baccarelli 42, Ma'en Obeidat 43, Myriam Fornage 44,45, Tianyuan Wang 46, James M Ward 46, Alison A Motsinger-Reif 47, Gibran Hemani 15,16, Gerard H Koppelman 8,14, Jordana T Bell 13, Sina A Gharib 12,48, Guy Brusselle 10,49,50, H Marike Boezen 7,8, Kari E North 6, Daniel Levy 3, Kathryn L Evans 4, Josée Dupuis 20, Charles E Breeze 51, Ani Manichaikul 11, Stephanie J London 1
1Epidemiology Branch.
2Department of Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts.
3Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, Framingham, Massachusetts.
4Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer and.
5Department of Population Health Sciences, Geisinger, Danville, Pennsylvania.
6Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina.
7Department of Epidemiology.
8Groningen Research Institute for Asthma and COPD, and.
9Department of Bioanalysis, Ghent University, Ghent, Belgium.
10Department of Epidemiology and.
11Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
12Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine.
13Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
14Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
15Medical Research Council Integrative Epidemiology Unit and.
16Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
17Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, and.
18Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
19Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York.
20Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
21Centre for Individualised Infection Medicine, a joint venture between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
22Research Group Bioinformatics and Computational Genomics, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
23Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
24Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
25Lothian Birth Cohorts Group, Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom.
26Cardiovascular Health Research Unit, Division of Cardiology, Department of Epidemiology.
27Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
28Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan.
29Department of Environmental Health and.
30Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
31Channing Laboratory, Harvard Medical School, Boston, Massachusetts.
32Department of Mathematics and Statistics, Old Dominion University, Norfolk, Virginia.
33National Heart and Lung Institute, Imperial College London, London, United Kingdom.
34Department of Preventive Medicine and.
35Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, California.
36Cardiovascular Health Research Unit, Department of Biostatistics.
37Veterans Affairs Boston Healthcare System, School of Medicine and School of Public Health, Boston University, Boston, Massachusetts.
38Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina.
39Department of Medicine and.
40Department of Epidemiology, Columbia University Medical Center, New York, New York.
41Department of Epidemiology, University of Colorado, Aurora, Colorado.
42Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York.
43Centre for Heart Lung Innovation, The University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada.
44Brown Foundation Institute of Molecular Medicine, McGovern Medical School, and.
45Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas.
46Integrative Bioinformatics Support Group, and.
47Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina.
48Computational Medicine Core, Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, Washington.
49Department of Respiratory Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
50Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; and.
51Altius Institute for Biomedical Sciences, Seattle, Washington.
Corresponding Author: Stephanie J. London
Abstract
Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication.
Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function.
Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics.
Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci.
Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.
논문정보
- Research article
- 2022년 08월 (BRIC 등록일 2024-01-31)
- 국외 연구진
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