Dataset Information

Genome-wide association of copy-number variation reveals an association between short stature and the presence of low-frequency genomic deletions.

ABSTRACT: Height is a model polygenic trait that is highly heritable. Genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with stature, but the role of structural variation in determining height is largely unknown. We performed a genome-wide association study of copy-number variation and stature in a clinical cohort of children who had undergone comparative genomic hybridization (CGH) microarray analysis for clinical indications. We found that subjects with short stature had a greater global burden of copy-number variants (CNVs) and a greater average CNV length than did controls (p < 0.002). These associations were present for lower-frequency (<5%) and rare (<1%) deletions, but there were no significant associations seen for duplications. Known gene-deletion syndromes did not account for our findings, and we saw no significant associations with tall stature. We then extended our findings into a population-based cohort and found that, in agreement with the clinical cohort study, an increased burden of lower-frequency deletions was associated with shorter stature (p = 0.015). Our results suggest that in individuals undergoing copy-number analysis for clinical indications, short stature increases the odds that a low-frequency deletion will be found. Additionally, copy-number variation might contribute to genetic variation in stature in the general population.

SUBMITTER: Dauber A

PROVIDER: S-EPMC3234379 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Genome-wide association of copy-number variation reveals an association between short stature and the presence of low-frequency genomic deletions.

Dauber Andrew A Yu Yongguo Y Turchin Michael C MC Chiang Charleston W CW Meng Yan A YA Demerath Ellen W EW Patel Sanjay R SR Rich Stephen S SS Rotter Jerome I JI Schreiner Pamela J PJ Wilson James G JG Shen Yiping Y Wu Bai-Lin BL Hirschhorn Joel N JN

American journal of human genetics 20111123 6

Height is a model polygenic trait that is highly heritable. Genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with stature, but the role of structural variation in determining height is largely unknown. We performed a genome-wide association study of copy-number variation and stature in a clinical cohort of children who had undergone comparative genomic hybridization (CGH) microarray analysis for clinical indications. We found that subjects wi ...[more]

PMID: 22118881

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Project description:BACKGROUND: Advances made in the area of microarray comparative genomic hybridization (aCGH) have enabled the interrogation of the entire genome at a previously unattainable resolution. This has lead to the discovery of a novel class of alternative entities called large-scale copy number variations (CNVs). These CNVs are often found in regions of closely linked sequence homology called duplicons that are thought to facilitate genomic rearrangements in some classes of neoplasia. Recently, it was proposed that duplicons located near the recurrent translocation break points on chromosomes 9 and 22 in chronic myeloid leukemia (CML) may facilitate this tumor-specific translocation. Furthermore, approximately 15-20% of CML patients also carry a microdeletion on the derivative 9 chromosome (der(9)) and these patients have a poor prognosis. It has been hypothesised that der(9) deletion patients have increased levels of chromosomal instability. RESULTS: In this study aCGH was performed and identified a CNV (RP11-125A5, hereafter called CNV14q12) that was present as a genomic gain or loss in 10% of control DNA samples derived from cytogenetically normal individuals. CNV14q12 was the same clone identified by Iafrate et al. as a CNV. Real-time polymerase chain reaction (Q-PCR) was used to determine the relative frequency of this CNV in DNA from a series of 16 CML patients (both with and without a der(9) deletion) together with DNA derived from 36 paediatric solid tumors in comparison to the incidence of CNV in control DNA. CNV14q12 was present in approximately 50% of both tumor and CML DNA, but was found in 72% of CML bearing a der(9) microdeletion. Chi square analysis found a statistically significant difference (p <or= 0.001) between the incidence of this CNV in cancer and normal DNA and a slightly increased incidence in CML with deletions in comparison to those CML without a detectable deletion. CONCLUSION: The increased incidence of CNV14q12 in tumor samples suggests that either acquired or inherited genomic variation of this new class of variation may be associated with onset or progression of neoplasia.

Dataset Information

Genome-wide association of copy-number variation reveals an association between short stature and the presence of low-frequency genomic deletions.

Publications

Genome-wide association of copy-number variation reveals an association between short stature and the presence of low-frequency genomic deletions.

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