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BMC Genet. 2016 Aug 11;17(1):116. doi: 10.1186/s12863-016-0423-0.

Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity.

Author information

1
Department of Health Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK.
2
National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
3
Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany.
4
DZHK (German Center for Cardiovascular Research), partner site Greifswald, 17475, Greifswald, Germany.
5
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Australia.
6
Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, 33521, Finland.
7
Department of Clinical Physiology, Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital, Turku, 20521, Finland.
8
School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
9
Division of Population Health Sciences, St. George's University of London, London, UK.
10
Department of Internal Medicine B - Pulmonary Medicine, Weaning and Infectious Diseases and Scientific Division of Pneumology and Pneumological Epidemiology, University Medicine Greifswald, Greifswald, Germany.
11
Department of Internal Medicine B - Cardiology, University Medicine Greifswald, Greifswald, Germany.
12
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
13
School of Social and Community Medicine, University of Bristol, Bristol, UK.
14
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
15
School of Public Health, University of Adelaide, Adelaide, Australia.
16
Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
17
Pfizer Worldwide Research and Development, Sollentuna, Sweden.
18
Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
19
Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
20
Department of Health Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK. louisewain@leicester.ac.uk.
21
National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK. louisewain@leicester.ac.uk.

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.

KEYWORDS:

Copy number variation; Genome-wide association study; Lung function

PMID:
27514831
PMCID:
PMC4981989
DOI:
10.1186/s12863-016-0423-0
[Indexed for MEDLINE]
Free PMC Article

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