title: Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
  
  
  METHODS
  We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
  
  
  RESULTS
  The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
  
  
  CONCLUSIONS
  In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
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authors.affiliation: University of Leicester, Genetic Epidemiology Group, Department of Health Sciences, Leicester, United Kingdom; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
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authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
authors.forename: Susan R
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authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Myriam
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authors.lastname: Fornage
authors.affiliation: University of Leicester, Genetic Epidemiology Group, Department of Health Sciences, Leicester, United Kingdom; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Section of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: George T
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authors.lastname: O'Connor
authors.affiliation: Division of Respiratory Medicine, University Hospital of Nottingham, Nottingham, United Kingdom.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Hall
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America; Department of Health Care Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, New York, United States of America.
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mesh_terms: D000328:Adult; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D012119:Respiration / Q000235:genetics*