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

Abstract

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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References

  1. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009)

    Article  CAS  ADS  Google Scholar 

  2. Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 10, 451–481 (2009)

    Article  CAS  Google Scholar 

  3. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007)

    Article  CAS  ADS  Google Scholar 

  4. Stankiewicz, P. & Beaudet, A. L. Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr. Opin. Genet. Dev. 17, 182–192 (2007)

    Article  CAS  Google Scholar 

  5. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008)

    Article  CAS  ADS  Google Scholar 

  6. The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008)

  7. McCarroll, S. A. et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nature Genet. 40, 1107–1112 (2008)

    Article  CAS  Google Scholar 

  8. Willer, C. J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genet. 41, 25–34 (2009)

    Article  CAS  Google Scholar 

  9. de Cid, R. et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nature Genet. 41, 211–215 (2009)

    Article  CAS  Google Scholar 

  10. Hollox, E. J. et al. Psoriasis is associated with increased β-defensin genomic copy number. Nature Genet. 40, 23–25 (2008)

    Article  CAS  Google Scholar 

  11. Diskin, S. J. et al. Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459, 987–991 (2009)

    Article  CAS  ADS  Google Scholar 

  12. Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 10.1038/nature08516 (7 October 2009)

  13. Murray, C. J. & Lopez, A. D. Evidence-based health policy–lessons from the Global Burden of Disease Study. Science 274, 740–743 (1996)

    Article  CAS  ADS  Google Scholar 

  14. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007)

  15. McCarroll, S. A. & Altshuler, D. M. Copy-number variation and association studies of human disease. Nature Genet. 39, S37–S42 (2007)

    Article  CAS  Google Scholar 

  16. Locke, D. P. et al. Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome. Am. J. Hum. Genet. 79, 275–290 (2006)

    Article  CAS  Google Scholar 

  17. McCarroll, S. A. et al. Common deletion polymorphisms in the human genome. Nature Genet. 38, 86–92 (2006)

    Article  CAS  Google Scholar 

  18. Barnes, C. et al. A robust statistical method for case-control association testing with copy number variation. Nature Genet. 40, 1245–1252 (2008)

    Article  CAS  Google Scholar 

  19. Horton, R. et al. Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project. Immunogenetics 60, 1–18 (2008)

    Article  CAS  Google Scholar 

  20. Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature Genet. 40, 638–645 (2008)

    Article  CAS  Google Scholar 

  21. Stefansson, H. et al. A common inversion under selection in Europeans. Nature Genet. 37, 129–137 (2005)

    Article  CAS  Google Scholar 

  22. Fanciulli, M. et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nature Genet. 39, 721–723 (2007)

    Article  CAS  Google Scholar 

  23. Mamtani, M. et al. CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus. Ann. Rheum. Dis. 67, 1076–1083 (2008)

    Article  CAS  Google Scholar 

  24. McKinney, C. et al. Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis. Ann. Rheum. Dis. 67, 409–413 (2008)

    Article  CAS  Google Scholar 

  25. Wilcoxon, F. Individual comparisons by ranking methods. Biom. Bull. 1, 80–83 (1945)

    Article  Google Scholar 

  26. Clayton, D. G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nature Genet. 37, 1243–1246 (2005)

    Article  CAS  Google Scholar 

  27. Field, S. F. et al. Experimental aspects of copy number variant assays at CCL3L1. Nature Med. 15, 1115–1117 (2009)

    Article  CAS  Google Scholar 

  28. Lieber, M. R., Yu, K. & Raghavan, S. C. Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair 5, 1234–1245 (2006)

    Article  CAS  Google Scholar 

  29. International HapMap Project. 〈http://hapmap.ncbi.nlm.nih.gov/〉 (2010)

  30. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006)

    Article  CAS  ADS  Google Scholar 

  31. Levy, S. et al. The diploid genome sequence of an individual human. PLoS Biol. 5, e254 (2007)

    Article  Google Scholar 

  32. Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008)

    Article  CAS  ADS  Google Scholar 

  33. McCarroll, S. A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. 40, 1166–1174 (2008)

    Article  CAS  Google Scholar 

  34. Koch, S. et al. Association of multiple sclerosis with ILT6 deficiency. Genes Immun. 6, 445–447 (2005)

    Article  CAS  Google Scholar 

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Acknowledgements

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 http://www.wtccc.org.uk/wtcccplus_cnv/supplemental.shtml. Full data are available, under a data access mechanism, from the European Genome-phenome Archive (http://www.ebi.ac.uk/ega/page.php).

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). https://doi.org/10.1038/nature08979

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