Abstract
BackgroundGenome-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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0423-0) contains supplementary material, which is available to authorized users.
Highlights
Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 single nucleotide polymorphism (SNP) associated with lung function
The total number of copy number variable region (CNVR) called and the proportions of deletions, amplifications and multiallelic CNVRs called in each cohort varied across genotyping platforms (Table 1) and we only meta-analysed CNVRs that were called consistently across platforms
As CNVCALL was able to resolve the largest proportion of the 2788 CNVRs as polymorphic in the busselton health study (BHS) cohort data (1962 CNVRs, 70.4 %) and the clustering gave the best separation of classes in the BHS data (Additional file 1), the number of classes called in the BHS cohort was used as our best estimate of the true number of classes and as the standard for calling copy number variant (CNV) genotypes with a consistent number of classes across all cohorts
Summary
Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. 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. Genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) have highlighted genes and biological pathways associated with risk of a variety of diseases and variability in quantitative health-related traits. Quantitative lung function traits are of major public health relevance and large GWAS have identified multiple common variants which collectively explain only a small proportion of the phenotypic variance. No genome-wide survey of the effect(s) of copy-number variants on lung function quantitative traits has been carried out
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