期刊
PLOS GENETICS
卷 8, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003098
关键词
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资金
- Intramural Research Program of the National Institutes of Health (NIH)
- National Institute of Environmental Health Sciences (NIEHS) [Z01ES043012]
- National Heart, Lung, and Blood Institute (NHLBI) [HL105756]
- UK MRC Senior Clinical Fellowship [G0902313]
- MRC [G1000861]
- NIH [N01-AG-12100, HHSN268200625226C, HHSN268200782096C]
- Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- NHLBI [HL105756, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-45204, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL075366, HL087652, N01-HC-25195, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, R01-HL077612, RC1-HL100543, N02-HL-6-4278]
- National Human Genome Research Institute (NHGRI) [U01HG004402]
- a component of the NIH and NIH Roadmap for Medical Research [UL1RR025005]
- Medical Research Council [G0000934]
- Wellcome Trust [068545/Z/02, 076113/B/04/Z]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- National Institute of Allergy and Infectious Diseases
- NHGRI
- National Institute of Child Health and Human Development
- Juvenile Diabetes Research Foundation International
- National Institute for Health Research Cambridge Biomedical Research Centre
- Wellcome Trust Strategic Award [079895]
- NHGRI [U01-HG-004729, U01-HG-004446, U01-HG-004424]
- M Fornage Cardiovascular Health Study (CHS) [U01-HG-004729, R01-HL-084099]
- National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058]
- Cedars-Sinai Board of Governors' Chair in Medical Genetics
- National Center for Research Resources CTSI [UL 1RR033176]
- NIDDK grant [DK063491]
- European Union (GABRIEL) [018996]
- European Union (ECRHS II Coordination) [QLK4-CT-1999-01237]
- Cancer Research UK
- Medical Research Council
- Affymetrix [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI)
- NIA [N01AG62101, N01AG2103, N01AG62106, 1R01AG032098-01A1]
- Intramural Research Program of NIA
- Intramural Research Programs of the NHGRI
- Netherlands Organization of Scientific Research NWO [175.010.2007.006]
- Economic Structure Enhancing Fund (FES) of the Dutch government
- Ministry of Economic Affairs
- Ministry of Education, Culture, and Science
- Ministry for Health, Welfare, and Sports
- Northern Netherlands Collaboration of Provinces (SNN)
- Province of Groningen
- University Medical Center Groningen
- University of Groningen
- Dutch Kidney Foundation
- Dutch Diabetes Research Foundation
- Academy of Finland (Center of Excellence in Complex Disease Genetics and SALVE) [104781, 120315, 129269, 1114194]
- University Hospital Oulu
- Biocenter
- University of Oulu, Finland [75617]
- NHLBI grant through the STAMPEED program [5R01HL087679-02, 1RL1MH083268-01]
- NIH/National Institute of Mental Health [5R01MH63706:02]
- ENGAGE project [HEALTH-F4-2007-201413]
- Medical Research Council, UK (PrevMetSyn/SALVE)
- NIHR Comprehensive Biomedical Research Centre
- Imperial College Healthcare NHS Trust
- Netherlands Organisation for Scientific Research (NWO) Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]
- Netherlands Genomics Initiative (NGI)/NWO [050-060-810]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- European Commission (DG XII)
- Municipality of Rotterdam
- Swiss National Science Foundation [3347CO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 32-65896.01, 32-59302.99, 32-52720.97, 32-4253.94, 4026-28099, PDFMP3-123171]
- Federal Office for Forest, Environment, and Landscape
- Federal Office of Public Health
- Federal Office of Roads and Transport
- canton's government of Aargau
- canton's government of Basel-Stadt
- canton's government of Basel-Land
- canton's government of Geneva
- canton's government of Luzern
- canton's government of Ticino
- canton's government of Zurich
- Swiss Lung League
- canton's Lung League of Basel Stadt/Basel Landschaft
- canton's Lung League of Geneva
- canton's Lung League of Ticino
- canton's Lung League of Zurich
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- German Asthma and COPD Network (COSYCONET)
- German Asthma and COPD Network (BMBP) [01GI0883]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Siemens Healthcare (Erlangen, Germany)
- Federal State of Mecklenburg-West Pomerania
- European Community's FP7 [HEALTH-F2-2008-201865-GEFOS]
- European Network of Genetic and Genomic Epidemiology (ENGAGE) [HEALTH-F4-2007-201413]
- FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]
- NIH/National Eye Institute [1RO1EY018246]
- [R21DK084529]
- [U01 DK062418]
- [RC1AG035835]
- [RR-024156]
- MRC [G0902313, G0000934, MC_U106188470, G1000861] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [PDFMP3-123171] Funding Source: Swiss National Science Foundation (SNF)
- Cancer Research UK [14136] Funding Source: researchfish
- Medical Research Council [G1000143, G0902313, G0401527, MC_U106188470, G1000861, MC_U106179471, G0801056B, G0000934] Funding Source: researchfish
- National Institute for Health Research [SRF/01/010] Funding Source: researchfish
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
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