title: Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity.
abstract: Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n < =12,403) with lung function measurements and meta-analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals.
  
  
  
  We generated robust copy number calls for 1962 out of 2788 (70 %) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P = 0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P = 0.004). In addition, we provide suggestive evidence (discovery P = 0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs.
  
  
  
  We demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits.
authors: Department of Health Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK.
authors: Nick
authors: 0000-0003-3641-4371
authors: N
authors: Shrine
authors: Department of Health Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK.|National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
authors: Martin D
authors: MD
authors: Tobin
authors: Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany.|DZHK (German Center for Cardiovascular Research), partner site Greifswald, 17475, Greifswald, Germany.
authors: Claudia
authors: C
authors: Schurmann
authors: Department of Health Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK.
authors: María
authors: M
authors: Soler Artigas
authors: Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Australia.
authors: Jennie
authors: J
authors: Hui
authors: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, 33521, Finland.
authors: Terho
authors: T
authors: Lehtimäki
authors: Department of Clinical Physiology, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital, Turku, 20521, Finland.
authors: Olli T
authors: OT
authors: Raitakari
authors: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
authors: Craig E
authors: CE
authors: Pennell
authors: School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
authors: Qi Wei
authors: QW
authors: Ang
authors: Division of Population Health Sciences, St. George's University of London, London, UK.
authors: David P
authors: DP
authors: Strachan
authors: Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany.
authors: Georg
authors: G
authors: Homuth
authors: Department of Internal Medicine B - Pulmonary Medicine, Weaning and Infectious Diseases and Scientific Division of Pneumology and Pneumological Epidemiology, University Medicine Greifswald, Greifswald, Germany.
authors: Sven
authors: S
authors: Gläser
authors: Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany.|Department of Internal Medicine B - Cardiology, University Medicine Greifswald, Greifswald, Germany.
authors: Stephan B
authors: SB
authors: Felix
authors: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.|University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: David M
authors: DM
authors: Evans
authors: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: John
authors: J
authors: Henderson
authors: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: Raquel
authors: R
authors: Granell
authors: School of Public Health, University of Adelaide, Adelaide, Australia.
authors: Lyle J
authors: LJ
authors: Palmer
authors: Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors: Jennifer
authors: J
authors: Huffman
authors: Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors: Caroline
authors: C
authors: Hayward
authors: Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors: Generation
authors: G
authors: Scotland
authors: Pfizer Worldwide Research and Development, Sollentuna, Sweden.
authors: Anders
authors: A
authors: Malarstig
authors: Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Australia.|Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
authors: Bill
authors: B
authors: Musk
authors: Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Australia.|Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
authors: Alan L
authors: AL
authors: James
authors: Department of Health Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK. louisewain@leicester.ac.uk.|National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK. louisewain@leicester.ac.uk.
authors: Louise V
authors: LV
authors: Wain
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics*; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008168:Lung; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D012129:Respiratory Function Tests; D014797:Vital Capacity / Q000235:genetics*; D055815:Young Adult
chemical_list: C417914:BANP protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins
keywords: Copy number variation; Genome-wide association study; Lung function