Vol. 73, No. 2, 2012
Issue release date: May 2012
Hum Hered 2012;73:84–94
(DOI:10.1159/000336982)
Original Paper
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ARIEL and AMELIA: Testing for an Accumulation of Rare Variants Using Next-Generation Sequencing Data

Asimit J.L.a · Day-Williams A.G.a · Morris A.P.b · Zeggini E.a
aWellcome Trust Sanger Institute, Hinxton, and bWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
email Corresponding Author


 goto top of outline Key Words

  • Whole-genome sequencing
  • Exome sequencing
  • Association analysis
  • Accounting for uncertainty
  • Complex trait

 goto top of outline Abstract

Objectives: There is increasing evidence that rare variants play a role in some complex traits, but their analysis is not straightforward. Locus-based tests become necessary due to low power in rare variant single-point association analyses. In addition, variant quality scores are available for sequencing data, but are rarely taken into account. Here, we propose two locus-based methods that incorporate variant quality scores: a regression-based collapsing approach and an allele-matching method. Methods: Using simulated sequencing data we compare 4 locus-based tests of trait association under different scenarios of data quality. We test two collapsing-based approaches and two allele-matching-based approaches, taking into account variant quality scores and ignoring variant quality scores. We implement the collapsing and allele-matching approaches accounting for variant quality in the freely available ARIEL and AMELIA software. Results: The incorporation of variant quality scores in locus-based association tests has power advantages over weighting each variant equally. The allele-matching methods are robust to the presence of both protective and risk variants in a locus, while collapsing methods exhibit a dramatic loss of power in this scenario. Conclusions: The incorporation of variant quality scores should be a standard protocol when performing locus-based association analysis on sequencing data. The ARIEL and AMELIA software implement collapsing and allele-matching locus association analysis methods, respectively, that allow the incorporation of variant quality scores.

Copyright © 2012 S. Karger AG, Basel


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    External Resources

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    External Resources

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 goto top of outline Author Contacts

Eleftheria Zeggini
Wellcome Trust Sanger Institute
The Morgan Building, Wellcome Trust Genome Campus
Hinxton, Cambridge CB10 1HH (UK)
Tel. +44 122 349 6868, E-Mail Eleftheria@sanger.ac.uk


 goto top of outline Article Information

Received: July 14, 2011
Accepted after revision: January 24, 2012
Published online: March 22, 2012
Number of Print Pages : 11
Number of Figures : 4, Number of Tables : 2, Number of References : 18
Additional supplementary material is available online - Number of Parts : 1


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 73, No. 2, Year 2012 (Cover Date: May 2012)

Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


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