title: Integrative pathway genomics of lung function and airflow obstruction.
abstract: Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
authors.affiliation: Computational Medicine Core, Center for Lung Biology, Department of Medicine, sagharib@u.washington.edu.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Daan W
authors.initials: DW
authors.lastname: Loth
authors.affiliation: Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK, National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: María
authors.initials: M
authors.lastname: Soler Artigas
authors.affiliation: Computational Medicine Core, Center for Lung Biology.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Birkland
authors.affiliation: Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, MA, USA.
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.affiliation: Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK, National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: Louise V
authors.initials: LV
authors.lastname: Wain
authors.affiliation: Cardiovascular Health Research Unit.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: University of British Columbia, Centre for Heart Lung Innovation, Vancouver, BC, Canada.
authors.forename: Ma'en
authors.initials: M
authors.lastname: Obeidat
authors.affiliation: Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, Research Triangle Institute (RTI) International, Research Triangle Park, NC, USA.
authors.forename: Dana B
authors.initials: DB
authors.lastname: Hancock
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Tang
authors.affiliation: Institute of Genetic Epidemiology.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rawal
authors.affiliation: Department of Epidemiology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland, University of Basel, Basel, Switzerland.
authors.forename: Medea
authors.initials: M
authors.lastname: Imboden
authors.affiliation: MRC Human Genetics Unit, MRC IGMM.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Lies
authors.initials: L
authors.lastname: Lahousse
authors.affiliation: School of Public Health.
authors.forename: Alexessander C
authors.initials: AC
authors.lastname: Alves
authors.affiliation: Center for Public Health Genomics, Division of Biostatistics and Epidemiology, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Manichaikul
authors.affiliation: PathWest Laboratory Medicine WA, Nedlands, Australia, School of Pathology and Laboratory Medicine, School of Population Health, The University of Western Australia, Nedlands, Australia.
authors.forename: Jennie
authors.initials: J
authors.lastname: Hui
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Department of Medical and Molecular Genetics.
authors.forename: Adaikalavan
authors.initials: A
authors.lastname: Ramasamy
authors.affiliation: Iceland Heart Association, Kopavogur, Iceland, University of Iceland, Reykjavik, Iceland.
authors.forename: Albert Vernon
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Iceland Heart Association, Kopavogur, Iceland, University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.affiliation: MRC Human Genetics Unit, MRC IGMM.
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent St Woolloongabba, QLD 4102, Australia, MRC Integrative Epidemiology Unit, Oakfield Road, Oakfield Grove BS82BN, Bristol, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: Population Health Research Institute, St George's, University of London, London, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands, Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Internal Medicine B, Pneumology, Cardiology, Intensive Care and Infectious Diseases, University Hospital Greifswald, Greifswald, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Gläser
authors.affiliation: Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, Scotland, UK.
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Jing Hua
authors.initials: JH
authors.lastname: Zhao
authors.affiliation: Cardiovascular Health Research Unit, Department of Epidemiology, Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.affiliation: Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Jarvis
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland, University of Basel, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Probst-Hensch
authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.affiliation: Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.affiliation: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK, Institute of Health Sciences, Biocenter Oulu, University of Oulu, Oulu, Finland, Unit of Primary Care, Oulu University Hospital, Oulu, Finland, Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, MA, USA, The NHLBI's Framingham Heart Study, Framingham, MA, USA.
authors.forename: George T
authors.initials: GT
authors.lastname: O'Connor
authors.affiliation: Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA, Department of Healthcare Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cassano
authors.affiliation: Department of Twins Research and Genetic Epidemiology, King's College, London, UK.
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: The NHLBI's Framingham Heart Study, Framingham, MA, USA, Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: MRC Human Genetics Unit, MRC IGMM.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Department of Medicine, Cardiovascular Health Research Unit, Department of Epidemiology, Department of Health Services, University of Washington, Seattle, WA, USA, Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Division of Respiratory Medicine, University Hospital of Nottingham, Nottingham, UK.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Hall
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA and.
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
authors.affiliation: Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK, National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, National Institute of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
mesh_terms: D000402:Airway Obstruction / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D049109:Cell Proliferation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D007107:Immune System; D008168:Lung / Q000503:physiopathology*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D044465:White People / Q000235:genetics