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Title: Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity
Authors: Shrine, Nick
Tobin, Martin D.
Schurmann, Claudia
Soler Artigas, María
Hui, Jennie
Lehtimäki, Terho
Raitakari, Olli T.
Pennell, Craig E.
Ang, Qi Wei
Strachan, David P.
Homuth, Georg
Gläser, Sven
Felix, Stephan B.
Evans, David M.
Henderson, John
Granell, Raquel
Palmer, Lyle J.
Huffman, Jennifer
Hayward, Caroline
Scotland, Generation
Malarstig, Anders
Musk, Bill
James, Alan L.
Wain, Louise V.
First Published: 11-Aug-2016
Publisher: BioMed Central
Citation: BMC Genetics, 2016, 17:116
Abstract: BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
DOI Link: 10.1186/s12863-016-0423-0
eISSN: 1471-2156
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Health Sciences

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