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A robust statistical method for case-control association testing with copy number variation.

ABSTRACT: Copy number variation (CNV) is pervasive in the human genome and can play a causal role in genetic diseases. The functional impact of CNV cannot be fully captured through linkage disequilibrium with SNPs. These observations motivate the development of statistical methods for performing direct CNV association studies. We show through simulation that current tests for CNV association are prone to false-positive associations in the presence of differential errors between cases and controls, especially if quantitative CNV measurements are noisy. We present a statistical framework for performing case-control CNV association studies that applies likelihood ratio testing of quantitative CNV measurements in cases and controls. We show that our methods are robust to differential errors and noisy data and can achieve maximal theoretical power. We illustrate the power of these methods for testing for association with binary and quantitative traits, and have made this software available as the R package CNVtools.

SUBMITTER: Barnes C

PROVIDER: S-EPMC2784596 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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A robust statistical method for case-control association testing with copy number variation.

Barnes Chris C Plagnol Vincent V Fitzgerald Tomas T Redon Richard R Marchini Jonathan J Clayton David D Hurles Matthew E ME

Nature genetics 20080907 10

Copy number variation (CNV) is pervasive in the human genome and can play a causal role in genetic diseases. The functional impact of CNV cannot be fully captured through linkage disequilibrium with SNPs. These observations motivate the development of statistical methods for performing direct CNV association studies. We show through simulation that current tests for CNV association are prone to false-positive associations in the presence of differential errors between cases and controls, especia ...[more]

PMID: 18776912

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Project description:The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative disease locus. Most methods widely implemented for such analyses are vulnerable to several key demographic factors and deliver a poor statistical power for detecting genuine associations and also a high false positive rate. Here, we present a likelihood-based statistical approach that accounts properly for non-random nature of case-control samples in regard of genotypic distribution at the loci in populations under study and confers flexibility to test for genetic association in presence of different confounding factors such as population structure, non-randomness of samples etc.We implemented this novel method together with several popular methods in the literature of GWAS, to re-analyze recently published Parkinson's disease (PD) case-control samples. The real data analysis and computer simulation show that the new method confers not only significantly improved statistical power for detecting the associations but also robustness to the difficulties stemmed from non-randomly sampling and genetic structures when compared to its rivals. In particular, the new method detected 44 significant SNPs within 25 chromosomal regions of size?<?1 Mb but only 6 SNPs in two of these regions were previously detected by the trend test based methods. It discovered two SNPs located 1.18 Mb and 0.18 Mb from the PD candidates, FGF20 and PARK8, without invoking false positive risk.We developed a novel likelihood-based method which provides adequate estimation of LD and other population model parameters by using case and control samples, the ease in integration of these samples from multiple genetically divergent populations and thus confers statistically robust and powerful analyses of GWAS. On basis of simulation studies and analysis of real datasets, we demonstrated significant improvement of the new method over the non-parametric trend test, which is the most popularly implemented in the literature of GWAS.

Dataset Information

A robust statistical method for case-control association testing with copy number variation.

Publications

A robust statistical method for case-control association testing with copy number variation.

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