title: VTET: a variable threshold exact test for identifying disease-associated copy number variations enriched in short genomic regions.
abstract: 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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health Bethesda, MD, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health Bethesda, MD, USA.
authors.forename: Xiaohong R
authors.initials: XR
authors.lastname: Yang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health Bethesda, MD, USA.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health Bethesda, MD, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health Bethesda, MD, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
keywords: copy number varination; genome-wide association study; interval-based association test; lung cancer CNV analysis; variable threshold exact test