A linkage disequilibrium-based approach to selecting disease-associated rare variants.

Rare variants have increasingly been cited as major contributors in the disease etiology of several complex disorders. Recently, several approaches have been proposed for analyzing the association of rare variants with disease. These approaches include collapsing rare variants, summing rare variant...

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Autores principales:	Rajesh Talluri, Sanjay Shete
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8fb83e637e224cec8af5008b5e43de19
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spelling	oai:doaj.org-article:8fb83e637e224cec8af5008b5e43de192021-11-18T07:37:46ZA linkage disequilibrium-based approach to selecting disease-associated rare variants.1932-620310.1371/journal.pone.0069226https://doaj.org/article/8fb83e637e224cec8af5008b5e43de192013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874919/?tool=EBIhttps://doaj.org/toc/1932-6203Rare variants have increasingly been cited as major contributors in the disease etiology of several complex disorders. Recently, several approaches have been proposed for analyzing the association of rare variants with disease. These approaches include collapsing rare variants, summing rare variant test statistics within a particular locus to improve power, and selecting a subset of rare variants for association testing, e.g., the step-up approach. We found that (a) if the variants being pooled are in linkage disequilibrium, the standard step-up method of selecting the best subset of variants results in loss of power compared to a model that pools all rare variants and (b) if the variants are in linkage equilibrium, performing a subset selection using step-based selection methods results in a gain of power of association compared to a model that pools all rare variants. Therefore, we propose an approach to selecting the best subset of variants to include in the model that is based on the linkage disequilibrium pattern among the rare variants. The proposed linkage disequilibrium-based variant selection model is flexible and borrows strength from the model that pools all rare variants when the rare variants are in linkage disequilibrium and from step-based selection methods when the variants are in linkage equilibrium. We performed simulations under three different realistic scenarios based on: (1) the HapMap3 dataset of the DRD2 gene, and CHRNA3/A5/B4 gene cluster (2) the block structure of linkage disequilibrium, and (3) linkage equilibrium. We proposed a permutation-based approach to control the type 1 error rate. The power comparisons after controlling the type 1 error show that the proposed linkage disequilibrium-based subset selection approach is an attractive alternative method for subset selection of rare variants.Rajesh TalluriSanjay ShetePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e69226 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rajesh Talluri Sanjay Shete A linkage disequilibrium-based approach to selecting disease-associated rare variants.
description	Rare variants have increasingly been cited as major contributors in the disease etiology of several complex disorders. Recently, several approaches have been proposed for analyzing the association of rare variants with disease. These approaches include collapsing rare variants, summing rare variant test statistics within a particular locus to improve power, and selecting a subset of rare variants for association testing, e.g., the step-up approach. We found that (a) if the variants being pooled are in linkage disequilibrium, the standard step-up method of selecting the best subset of variants results in loss of power compared to a model that pools all rare variants and (b) if the variants are in linkage equilibrium, performing a subset selection using step-based selection methods results in a gain of power of association compared to a model that pools all rare variants. Therefore, we propose an approach to selecting the best subset of variants to include in the model that is based on the linkage disequilibrium pattern among the rare variants. The proposed linkage disequilibrium-based variant selection model is flexible and borrows strength from the model that pools all rare variants when the rare variants are in linkage disequilibrium and from step-based selection methods when the variants are in linkage equilibrium. We performed simulations under three different realistic scenarios based on: (1) the HapMap3 dataset of the DRD2 gene, and CHRNA3/A5/B4 gene cluster (2) the block structure of linkage disequilibrium, and (3) linkage equilibrium. We proposed a permutation-based approach to control the type 1 error rate. The power comparisons after controlling the type 1 error show that the proposed linkage disequilibrium-based subset selection approach is an attractive alternative method for subset selection of rare variants.
format	article
author	Rajesh Talluri Sanjay Shete
author_facet	Rajesh Talluri Sanjay Shete
author_sort	Rajesh Talluri
title	A linkage disequilibrium-based approach to selecting disease-associated rare variants.
title_short	A linkage disequilibrium-based approach to selecting disease-associated rare variants.
title_full	A linkage disequilibrium-based approach to selecting disease-associated rare variants.
title_fullStr	A linkage disequilibrium-based approach to selecting disease-associated rare variants.
title_full_unstemmed	A linkage disequilibrium-based approach to selecting disease-associated rare variants.
title_sort	linkage disequilibrium-based approach to selecting disease-associated rare variants.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/8fb83e637e224cec8af5008b5e43de19
work_keys_str_mv	AT rajeshtalluri alinkagedisequilibriumbasedapproachtoselectingdiseaseassociatedrarevariants AT sanjayshete alinkagedisequilibriumbasedapproachtoselectingdiseaseassociatedrarevariants AT rajeshtalluri linkagedisequilibriumbasedapproachtoselectingdiseaseassociatedrarevariants AT sanjayshete linkagedisequilibriumbasedapproachtoselectingdiseaseassociatedrarevariants
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A linkage disequilibrium-based approach to selecting disease-associated rare variants.

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