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Copy-number variation and association studies of human disease

Abstract

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.

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McCarroll, S., Altshuler, D. Copy-number variation and association studies of human disease. Nat Genet 39, S37–S42 (2007). https://doi.org/10.1038/ng2080

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