Detection, Imputation, and Association Analysis of Small Deletions and Null Alleles on Oligonucleotide Arrays

Abstract

Copy-number variation (CNV) is a major contributor to human genetic variation. Recently, CNV associations with human disease have been reported. Many genome-wide association (GWA) studies in complex diseases have been performed with sets of biallelic single-nucleotide polymorphisms (SNPs), but the available CNV methods are still limited. We present a new method (TriTyper) that can infer genotypes in case-control data sets for deletion CNVs, or SNPs with an extra, untyped allele at a high-resolution single SNP level. By accounting for linkage disequilibrium (LD), as well as intensity data, calling accuracy is improved. Analysis of 3102 unrelated individuals with European descent, genotyped with Illumina Infinium BeadChips, resulted in the identification of 1880 SNPs with a common untyped allele, and these SNPs are in strong LD with neighboring biallelic SNPs. Simulations indicate our method has superior power to detect associations compared to biallelic SNPs that are in LD with these SNPs, yet without increasing type I errors, as shown in a GWA analysis in celiac disease. Genotypes for 1204 triallelic SNPs could be fully imputed, with only biallelic-genotype calls, permitting association analysis of these SNPs in many published data sets. We estimate that 682 of the 1655 unique loci reflect deletions; this is on average 99 deletions per individual, four times greater than those detected by other methods. Whereas the identified loci are strongly enriched for known deletions, 61% have not been reported before. Genes overlapping with these loci more often have paralogs (p = 0.006) and biologically interact with fewer genes than expected (p = 0.004).

Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syndrome

“…Another limitation is that we assumed a single copy number change caused KS. It remains to be elucidated that whether CNV association 25 contribute to manifestations of KS. If the further investigation with refined array technologies could not find the etiology of KS, the direction of study for KS will have to be changed to find de novo sequence alteration or methylation aberration including even in the noncoding genomic regions.…”

Copy number variation and susceptibility to human disorders (Review)

“…In this method, SNPs and CNVs are used together for association studies (50,51). Recently, microarray CGH has also been used.…”

Novel Altered Region for Biomarker Discovery in Hepatocellular Carcinoma (HCC) Using Whole Genome SNP Array

“…Cooper et al use SNP conditional mixture modelling (SCIMM) by applied a mixture-likelihood clustering method within the R statistical package to identify deletions of copy number changes [19]. Franke et al present a combined approach focus on single SNP interpretation; Trityper uses maximum likelihood estimation to detect deletions in Illumina SNP data in unrelated samples [20].…”