Genetic association studies of copy-number variation: should assignment of copy number states precede testing?

Patrick Breheny; Prabhakar Chalise; Anthony Batzler; Liewei Wang; Brooke L Fridley

doi:10.1371/journal.pone.0034262

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Genetic association studies of copy-number variation: should assignment of copy number states precede testing?

Journal article

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Genetic association studies of copy-number variation: should assignment of copy number states precede testing?

Patrick Breheny, Prabhakar Chalise, Anthony Batzler, Liewei Wang and Brooke L Fridley

PloS one, Vol.7(4), pp.e34262-e34262

2012

DOI: 10.1371/journal.pone.0034262

PMCID: PMC3320903

PMID: 22493684

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Abstract

Recently, structural variation in the genome has been implicated in many complex diseases. Using genomewide single nucleotide polymorphism (SNP) arrays, researchers are able to investigate the impact not only of SNP variation, but also of copy-number variants (CNVs) on the phenotype. The most common analytic approach involves estimating, at the level of the individual genome, the underlying number of copies present at each location. Once this is completed, tests are performed to determine the association between copy number state and phenotype. An alternative approach is to carry out association testing first, between phenotype and raw intensities from the SNP array at the level of the individual marker, and then aggregate neighboring test results to identify CNVs associated with the phenotype. Here, we explore the strengths and weaknesses of these two approaches using both simulations and real data from a pharmacogenomic study of the chemotherapeutic agent gemcitabine. Our results indicate that pooled marker-level testing is capable of offering a dramatic increase in power (> 12-fold) over CNV-level testing, particularly for small CNVs. However, CNV-level testing is superior when CNVs are large and rare; understanding these tradeoffs is an important consideration in conducting association studies of structural variation.

Data Interpretation, Statistical

Deoxycytidine - genetics

Oligonucleotide Array Sequence Analysis

Humans

Deoxycytidine - pharmacology

Genotype

DNA Copy Number Variations - genetics

Genetic Markers

Genome-Wide Association Study - statistics & numerical data

Genetic Variation

Phenotype

Algorithms

Computer Simulation

Polymorphism, Single Nucleotide - genetics

Genome, Human

Deoxycytidine - analogs & derivatives

Pharmacogenetics - statistics & numerical data

Details

Title: Subtitle: Genetic association studies of copy-number variation: should assignment of copy number states precede testing?
Creators: Patrick Breheny - Department of Biostatistics, University of Kentucky, Lexington, Kentucky, United States of America. patrick.breheny@uky.edu
Prabhakar Chalise
Anthony Batzler
Liewei Wang
Brooke L Fridley
Resource Type: Journal article
Publication Details: PloS one, Vol.7(4), pp.e34262-e34262
DOI: 10.1371/journal.pone.0034262
PMID: 22493684
PMCID: PMC3320903
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: United States
Grant note: U01 GM061388 / NIGMS NIH HHS R21 CA140879 / NCI NIH HHS U19 GM061388 / NIGMS NIH HHS R21 GM086689 / NIGMS NIH HHS K22 CA130828 / NCI NIH HHS R01 CA138461 / NCI NIH HHS
Language: English
Date published: 2012
Academic Unit: Biostatistics
Record Identifier: 9983997488002771

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