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Genome-wide analysis of copy number variation in type 1 diabetes.

ABSTRACT: Type 1 diabetes (T1D) tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs). We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl) cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D.

SUBMITTER: Grayson BL

PROVIDER: S-EPMC2981564 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Genome-wide analysis of copy number variation in type 1 diabetes.

Grayson Britney L BL Smith Mary Ellen ME Thomas James W JW Wang Lily L Dexheimer Phil P Jeffrey Joy J Fain Pamela R PR Nanduri Priyaanka P Eisenbarth George S GS Aune Thomas M TM

PloS one 20101115 11

Type 1 diabetes (T1D) tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs). We performed genome-wide CNV analysis on a cohort of ...[more]

PMID: 21085585

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Project description:BackgroundIn this work, our aim was to generate a map of the copy number variations (CNV) segregating in a population of Murciano-Granadina goats, the most important dairy breed in Spain, and to ascertain the main biological functions of the genes that map to copy number variable regions.ResultsUsing a dataset that comprised 1036 Murciano-Granadina goats genotyped with the Goat SNP50 BeadChip, we were able to detect 4617 and 7750 autosomal CNV with the PennCNV and QuantiSNP software, respectively. By applying the EnsembleCNV algorithm, these CNV were assembled into 1461 CNV regions (CNVR), of which 486 (33.3% of the total CNVR count) were consistently called by PennCNV and QuantiSNP and used in subsequent analyses. In this set of 486 CNVR, we identified 78 gain, 353 loss and 55 gain/loss events. The total length of all the CNVR (95.69 Mb) represented 3.9% of the goat autosomal genome (2466.19 Mb), whereas their size ranged from 2.0 kb to 11.1 Mb, with an average size of 196.89 kb. Functional annotation of the genes that overlapped with the CNVR revealed an enrichment of pathways related with olfactory transduction (fold-enrichment = 2.33, q-value = 1.61 × 10-10), ABC transporters (fold-enrichment = 5.27, q-value = 4.27 × 10-04) and bile secretion (fold-enrichment = 3.90, q-value = 5.70 × 10-03).ConclusionsA previous study reported that the average number of CNVR per goat breed was ~ 20 (978 CNVR/50 breeds), which is much smaller than the number we found here (486 CNVR). We attribute this difference to the fact that the previous study included multiple caprine breeds that were represented by small to moderate numbers of individuals. Given the low frequencies of CNV (in our study, the average frequency of CNV is 1.44%), such a design would probably underestimate the levels of the diversity of CNV at the within-breed level. We also observed that functions related with sensory perception, metabolism and embryo development are overrepresented in the set of genes that overlapped with CNV, and that these loci often belong to large multigene families with tens, hundreds or thousands of paralogous members, a feature that could favor the occurrence of duplications or deletions by non-allelic homologous recombination.

Dataset Information

Genome-wide analysis of copy number variation in type 1 diabetes.

Publications

Genome-wide analysis of copy number variation in type 1 diabetes.

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