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Copy-number variation and association studies of human disease


The central goal of human genetics is to understand the inherited basis of human variation in phenotypes, elucidating human physiology, evolution and disease. Rare mutations have been found underlying two thousand mendelian diseases; more recently, it has become possible to assess systematically the contribution of common SNPs to complex disease. The known role of copy-number alterations in sporadic genomic disorders, combined with emerging information about inherited copy-number variation, indicate the importance of systematically assessing copy-number variants (CNVs), including common copy-number polymorphisms (CNPs), in disease. Here we discuss evidence that CNVs affect phenotypes, directions for basic knowledge to support clinical study of CNVs, the challenge of genotyping CNPs in clinical cohorts, the use of SNPs as markers for CNPs and statistical challenges in testing CNVs for association with disease. Critical needs are high-resolution maps of common CNPs and techniques that accurately determine the allelic state of affected individuals.

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Figure 1: Many potential CNV locations are consistent with the coordinates of a reported CNV-containing region (CNVR).
Figure 2: Although the number of reported copy-number-variable regions has increased dramatically, only a few percent of CNVs have been successfully genotyped.
Figure 3: Using copy-number measurements and copy-number genotypes in association studies.


  1. 1

    Inoue, K. & Lupski, J.R. Molecular mechanisms for genomic disorders. Annu. Rev. Genomics Hum. Genet. 3, 199–242 (2002).

    CAS  Article  Google Scholar 

  2. 2

    Lupski, J. R. Genomic rearrangements and sporadic disease. Nat. Genet. 39, S43–S47 (2007).

    CAS  Article  Google Scholar 

  3. 3

    Padiath, Q.S. et al. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet. 38, 1114–1123 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Le Marechal, C. et al. Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat. Genet. 38, 1372–1374 (2006).

    CAS  Article  Google Scholar 

  5. 5

    Lee, J.A. & Lupski, J.R. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Gonzalez, E. et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Aitman, T.J. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851–855 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Yang, Y. et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. 80, 1037–1054 (2007).

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

    Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    CAS  Article  Google Scholar 

  11. 11

    de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

    CAS  Article  Google Scholar 

  12. 12

    Pe'er, I. et al. Evaluating and improving power in whole-genome association studies using fixed marker sets. Nat. Genet. 38, 663–667 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Altshuler, D. et al. An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 407, 513–516 (2000).

    CAS  Article  Google Scholar 

  14. 14

    Reich, D.E., Gabriel, S.B. & Altshuler, D. Quality and completeness of SNP databases. Nat. Genet. 33, 457–458 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Hinds, D.A. et al. Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079 (2005).

    CAS  Article  Google Scholar 

  16. 16

    International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  17. 17

    Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    CAS  Article  Google Scholar 

  18. 18

    Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Sharp, A.J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).

    CAS  Article  Google Scholar 

  20. 20

    Tuzun, E. et al. Fine-scale structural variation of the human genome. Nat. Genet. 37, 727–732 (2005).

    CAS  Article  Google Scholar 

  21. 21

    Conrad, D.F., Andrews, T.D., Carter, N.P., Hurles, M.E. & Pritchard, J.K. A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet. 38, 75–81 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Hinds, D.A., Kloek, A.P., Jen, M., Chen, X. & Frazer, K.A. Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat. Genet. 38, 82–85 (2006).

    CAS  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

    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).

    CAS  Article  Google Scholar 

  25. 25

    Khaja, R. et al. Genome assembly comparison identifies structural variants in the human genome. Nat. Genet. 38, 1413–1418 (2006).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

    Zhang, J., Feuk, L., Duggan, G.E., Khaja, R. & Scherer, S.W. Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenet. Genome Res. 115, 205–214 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Eichler, E.E. et al. Completing the map of human genetic variation. Nature 447, 161–165 (2007).

    CAS  Article  Google Scholar 

  29. 29

    Fiegler, H. et al. Accurate and reliable high-throughput detection of copy number variation in the human genome. Genome Res. 16, 1566–1574 (2006).

    CAS  Article  Google Scholar 

  30. 30

    McVean, G.A. et al. The fine-scale structure of recombination rate variation in the human genome. Science 304, 581–584 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    CAS  Article  Google Scholar 

  32. 32

    Lieberfarb, M.E. et al. Genome-wide loss of heterozygosity analysis from laser capture microdissected prostate cancer using single nucleotide polymorphic allele (SNP) arrays and a novel bioinformatics platform dChipSNP. Cancer Res. 63, 4781–4785 (2003).

    CAS  PubMed  Google Scholar 

  33. 33

    Zhao, X. et al. An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res. 64, 3060–3071 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Garraway, L.A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).

    CAS  Article  Google Scholar 

  35. 35

    Zhao, X. et al. Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res. 65, 5561–5570 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Cohen, J.C., Boerwinkle, E., Mosley, T.H., Jr. & Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

    CAS  Article  Google Scholar 

  38. 38

    Campbell, C.D. et al. Demonstrating stratification in a European American population. Nat. Genet. 37, 868–872 (2005).

    CAS  Article  Google Scholar 

  39. 39

    Pritchard, J.K., Stephens, M., Rosenberg, N.A. & Donnelly, P. Association mapping in structured populations. Am. J. Hum. Genet. 67, 170–181 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Article  Google Scholar 

  41. 41

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

    CAS  Article  Google Scholar 

  42. 42

    Lohmueller, K.E., Pearce, C.L., Pike, M., Lander, E.S. & Hirschhorn, J.N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177–182 (2003).

    CAS  Article  Google Scholar 

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

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