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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls


Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease—IRGM for Crohn’s disease, HLA for Crohn’s disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes—although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

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Figure 1: Flowchart showing which CNVs are included on the array.
Figure 2: Illustrative CNVs.
Figure 3: Genome-wide association results.


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The principal funder of this project was the Wellcome Trust. Many individuals, groups, consortia, organizations and funding bodies have made important contributions to sample collections and coordination of the scientific analyses. Details are provided in Supplementary Information Section 11. We are indebted to all those who participated within the sample collections.

Author Contributions are listed in Supplementary Information.

Author information

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Corresponding author

Correspondence to Peter Donnelly.

Additional information

Summary information for the CNVs studied, including genomic locations, numbers of classes and SNP tags on different platforms is available at Full data are available, under a data access mechanism, from the European Genome-phenome Archive (

Lists of authors and their affiliations appear at the end of the paper.

Supplementary information

Supplementary Information 1

This Supplementary Information file comprises: 1 Pilot study; 2 Samples; 3 CNV experiment, 4 Data and pre-processing; 5 Quality control procedures; 6 Calling and testing; 7 Properties of the CNV calls; 8 Replication and validation of associated CNVs in WTCCC; 9 Other analyses; 10 Glossary; 11 Acknowledgements; 12 Author contributions; 13 Supplementary Figures 1-33 with legends, 14 Tables 1-16 and Supplementary References. (PDF 10055 kb)

Supplementary Information 2

This file contains plots of CNV calls and association testing results produced by the CNVCALL/CNVTEST approach. (PDF 1196 kb)

Supplementary Information 3

This file contains plots of CNV calls and association testing results produced by the CNVtools approach. (PDF 756 kb)

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The Wellcome Trust Case Control Consortium. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).

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