Rare variant association testing for next-generation sequencing data via hierarchical clustering.

Content Provider	Europe PMC
Author	Tachmazidou, Ioanna Morris, Andrew Zeggini, Eleftheria
Copyright Year	2013
Abstract	Objectives It is thought that a proportion of the genetic susceptibility to complex diseases is due to low-frequency and rare variants. Next-generation sequencing in large populations facilitates the detection of rare variant associations to disease risk. In order to achieve adequate power to detect association at low-frequency and rare variants, locus-specific statistical methods are being developed that combine information across variants within a functional unit and test for association with this enriched signal through so-called burden tests. Methods We propose a hierarchical clustering approach and a similarity kernel-based association test for continuous phenotypes. This method clusters individuals into groups, within which samples are assumed to be genetically similar, and subsequently tests the group effects among the different clusters. Results The power of this approach is comparable to that of collapsing methods when causal variants have the same direction of effect, but its power is significantly higher compared to burden tests when both protective and risk variants are present in the region of interest. Overall, we observe that the Sequence Kernel Association Test (SKAT) is the most powerful approach under the allelic architectures considered. Conclusions In our overall comparison, we find the analytical framework within which SKAT operates to yield higher power and to control type I error appropriately.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC3668801&blobtype=pdf
Page Count	7
ISSN	00015652
Volume Number	74
DOI	10.1159/000346022
PubMed Central reference number	PMC3668801
Issue Number	3-4
PubMed reference number	23594494
Journal	Human Heredity [Hum Hered]
e-ISSN	14230062
Language	English
Publisher	Karger Publishers
Publisher Date	2012-01-01
Publisher Place	Switzerland
Access Restriction	Open
Rights License	This is an Open Access article licensed under the terms of the Creative Commons Attribution 3.0 Unported license (CC BY 3.0) (www.karger.com/OA-license-WT), applicable to the online version of the article only. Users may download, print and share this work on the Internet, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions. Copyright © 2013 by S. Karger AG, Basel
Subject Keyword	Allele match kernel Genetic similarity Next-generation sequencing Single nucleotide polymorphism
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)