Methods ARTICLE

Front. Genet., 18 March 2014 | http://dx.doi.org/10.3389/fgene.2014.00053

VTET: a variable threshold exact test for identifying disease-associated copy number variations enriched in short genomic regions

Jianxin Shi*, Xiaohong R. Yang, Neil E. Caporaso, Maria T. Landi and Peng Li
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Copy number variations (CNVs) constitute a major source of genetic variations in human populations and have been reported to be associated with complex diseases. Methods have been developed for detecting CNVs and testing CNV associations in genome-wide association studies (GWAS) based on SNP arrays. Commonly used two-step testing procedures work well only for long CNVs while direct CNV association testing methods work only for recurrent CNVs. Assuming that short CNVs disrupting any part of a given genomic region increase disease risk, we developed a variable threshold exact test (VTET) for testing disease associations of CNVs randomly distributed in the genome using intensity data from SNP arrays. By extensive simulations, we found that VTET outperformed two-step testing procedures based on existing CNV calling algorithms for short CNVs and that the performance of VTET was robust to the length of the genomic region. In addition, VTET had a comparable performance with CNVtools for testing the association of recurrent CNVs. Thus, we expect VTET to be useful for testing disease associations of both recurrent and randomly distributed CNVs using existing GWAS data. We applied VTET to a lung cancer GWAS and identified a genome-wide significant region on chromosome 18q22.3 for lung squamous cell carcinoma.

Keywords: copy number varination, variable threshold exact test, genome-wide association study, interval-based association test, lung cancer CNV analysis

Citation: Shi J, Yang XR, Caporaso NE, Landi MT and Li P (2014) VTET: a variable threshold exact test for identifying disease-associated copy number variations enriched in short genomic regions. Front. Genet. 5:53. doi: 10.3389/fgene.2014.00053

Received: 09 January 2014; Accepted: 27 February 2014;
Published online: 18 March 2014.

Edited by:

Rui Feng, University of Pennsylvania, USA

Reviewed by:

Fang Yixin, New York University, USA
X. Jessie Jeng, North Carolina State University, USA

Copyright © 2014 Shi, Yang, Caporaso, Landi and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jianxin Shi, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Room 7E596, Bethesda, MD 20892, USA e-mail: jianxin.shi@nih.gov