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 approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 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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References

. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008; 455(7210):237-41. PMC: 3912847. DOI: 10.1038/nature07239. View

McCarroll S, Kuruvilla F, Korn J, Cawley S, Nemesh J, Wysoker A . Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008; 40(10):1166-74. DOI: 10.1038/ng.238. View

de Cid R, Riveira-Munoz E, Zeeuwen P, Robarge J, Liao W, Dannhauser E . Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet. 2009; 41(2):211-5. PMC: 3128734. DOI: 10.1038/ng.313. View

Conrad D, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y . Origins and functional impact of copy number variation in the human genome. Nature. 2009; 464(7289):704-12. PMC: 3330748. DOI: 10.1038/nature08516. View

Stankiewicz P, Beaudet A . Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev. 2007; 17(3):182-92. DOI: 10.1016/j.gde.2007.04.009. View

Levy S, Sutton G, Ng P, Feuk L, Halpern A, Walenz B . The diploid genome sequence of an individual human. PLoS Biol. 2007; 5(10):e254. PMC: 1964779. DOI: 10.1371/journal.pbio.0050254. View

Kidd J, Cooper G, Donahue W, Hayden H, Sampas N, Graves T . Mapping and sequencing of structural variation from eight human genomes. Nature. 2008; 453(7191):56-64. PMC: 2424287. DOI: 10.1038/nature06862. View

Hollox E, Huffmeier U, Zeeuwen P, Palla R, Lascorz J, Rodijk-Olthuis D . Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet. 2007; 40(1):23-5. PMC: 2447885. DOI: 10.1038/ng.2007.48. View

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View

10.

McCarroll S, Huett A, Kuballa P, Chilewski S, Landry A, Goyette P . Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet. 2009; 40(9):1107-12. PMC: 2731799. DOI: 10.1038/ng.215. View

11.

Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J . A common inversion under selection in Europeans. Nat Genet. 2005; 37(2):129-37. DOI: 10.1038/ng1508. View

12.

McCarroll S, Altshuler D . Copy-number variation and association studies of human disease. Nat Genet. 2007; 39(7 Suppl):S37-42. DOI: 10.1038/ng2080. View

13.

Stefansson H, Rujescu D, Cichon S, Pietilainen O, Ingason A, Steinberg S . Large recurrent microdeletions associated with schizophrenia. Nature. 2008; 455(7210):232-6. PMC: 2687075. DOI: 10.1038/nature07229. View

14.

Redon R, Ishikawa S, Fitch K, Feuk L, Perry G, Andrews T . Global variation in copy number in the human genome. Nature. 2006; 444(7118):444-54. PMC: 2669898. DOI: 10.1038/nature05329. View

15.

Zeggini E, Scott L, Saxena R, Voight B, Marchini J, Hu T . Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008; 40(5):638-45. PMC: 2672416. DOI: 10.1038/ng.120. View

16.

Zhang F, Gu W, Hurles M, Lupski J . Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009; 10:451-81. PMC: 4472309. DOI: 10.1146/annurev.genom.9.081307.164217. View

17.

Koch S, Goedde R, Nigmatova V, Epplen J, Muller N, De Seze J . Association of multiple sclerosis with ILT6 deficiency. Genes Immun. 2005; 6(5):445-7. DOI: 10.1038/sj.gene.6364187. View

18.

Barnes C, Plagnol V, Fitzgerald T, Redon R, Marchini J, Clayton D . A robust statistical method for case-control association testing with copy number variation. Nat Genet. 2008; 40(10):1245-52. PMC: 2784596. DOI: 10.1038/ng.206. View

19.

Lieber M, Yu K, Raghavan S . Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair (Amst). 2006; 5(9-10):1234-45. DOI: 10.1016/j.dnarep.2006.05.013. View

20.

Field S, Howson J, Maier L, Walker S, Walker N, Smyth D . Experimental aspects of copy number variant assays at CCL3L1. Nat Med. 2009; 15(10):1115-7. PMC: 2873561. DOI: 10.1038/nm1009-1115. View