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Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn's disease

Lookup NU author(s): Dr John Mansfield


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The copy number variation in beta-defensin genes on human chromosome 8 has been proposed to underlie susceptibility to inflammatory disorders, but presents considerable challenges for accurate typing on the scale required for adequately powered case-control studies. In this work, we have used accurate methods of copy number typing based on the paralogue ratio test (PRT) to assess beta-defensin copy number in more than 1500 UK DNA samples including more than 1000 cases of Crohn's disease. A subset of 625 samples was typed using both PRT-based methods and standard real-time PCR methods, from which direct comparisons highlight potentially serious shortcomings of a real-time PCR assay for typing this variant. Comparing our PRT-based results with two previous studies based only on real-time PCR, we find no evidence to support the reported association of Crohn's disease with either low or high beta-defensin copy number; furthermore, it is noteworthy that there are disagreements between different studies on the observed frequency distribution of copy number states among European controls. We suggest safeguards to be adopted in assessing and reporting the accuracy of copy number measurement, with particular emphasis on integer clustering of results, to avoid reporting of spurious associations in future case-control studies.

Publication metadata

Author(s): Aldhous MC, Abu Bakar S, Prescott NJ, Palla R, Soo K, Mansfield JC, Mathew CG, Satsangi J, Armour JAL

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2010

Volume: 19

Issue: 24

Pages: 4930-4938

Print publication date: 21/09/2010

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddq411


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Funder referenceFunder name
Chief Scientist's Office
Guy's and St Thomas' Charity
King's College London
National Institutes of Health Research Biomedical Research Centre at Guy's St Thomas' NHS Foundation Trust
Portuguese FCT
Scottish Government
Ministry of Higher Education, Malaysia
081808/CGMWellcome Trust