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Test for rare variants by environment interactions in sequencing association studies

We consider in this article testing rare variants by environment interactions in sequencing association studies. Current methods for studying the association of rare variants with traits cannot be readily applied for testing for rare variants by environment interactions, as these methods do not effe... Full description

Journal Title: Biometrics March 2016, Vol.72(1), pp.156-164
Main Author: Lin, Xinyi
Other Authors: Lee, Seunggeun , Wu, Michael C. , Wang, Chaolong , Chen, Han , Li, Zilin , Lin, Xihong
Format: Electronic Article Electronic Article
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ID: ISSN: 0006-341X ; E-ISSN: 1541-0420 ; DOI: 10.1111/biom.12368
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recordid: wj10.1111/biom.12368
title: Test for rare variants by environment interactions in sequencing association studies
format: Article
creator:
  • Lin, Xinyi
  • Lee, Seunggeun
  • Wu, Michael C.
  • Wang, Chaolong
  • Chen, Han
  • Li, Zilin
  • Lin, Xihong
subjects:
  • Bias Analysis
  • Gene–Environment Interactions
  • Sequencing Association Studies
ispartof: Biometrics, March 2016, Vol.72(1), pp.156-164
description: We consider in this article testing rare variants by environment interactions in sequencing association studies. Current methods for studying the association of rare variants with traits cannot be readily applied for testing for rare variants by environment interactions, as these methods do not effectively control for the main effects of rare variants, leading to unstable results and/or inflated Type 1 error rates. We will first analytically study the bias of the use of conventional burden-based tests for rare variants by environment interactions, and show the tests can often be invalid and result in inflated Type 1 error rates. To overcome these difficulties, we develop the interaction sequence kernel association test (iSKAT) for assessing rare variants by environment interactions. The proposed test iSKAT is optimal in a class of variance component tests and is powerful and robust to the proportion of variants in a gene that interact with environment and the signs of the effects. This test properly controls for the main effects of the rare variants using weighted ridge regression while adjusting for covariates. We demonstrate the performance of iSKAT using simulation studies and illustrate its application by analysis of a candidate gene sequencing study of plasma adiponectin levels.
language:
source:
identifier: ISSN: 0006-341X ; E-ISSN: 1541-0420 ; DOI: 10.1111/biom.12368
fulltext: fulltext
issn:
  • 0006-341X
  • 0006341X
  • 1541-0420
  • 15410420
url: Link


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titleTest for rare variants by environment interactions in sequencing association studies
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ispartofBiometrics, March 2016, Vol.72(1), pp.156-164
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descriptionWe consider in this article testing rare variants by environment interactions in sequencing association studies. Current methods for studying the association of rare variants with traits cannot be readily applied for testing for rare variants by environment interactions, as these methods do not effectively control for the main effects of rare variants, leading to unstable results and/or inflated Type 1 error rates. We will first analytically study the bias of the use of conventional burden-based tests for rare variants by environment interactions, and show the tests can often be invalid and result in inflated Type 1 error rates. To overcome these difficulties, we develop the interaction sequence kernel association test (iSKAT) for assessing rare variants by environment interactions. The proposed test iSKAT is optimal in a class of variance component tests and is powerful and robust to the proportion of variants in a gene that interact with environment and the signs of the effects. This test properly controls for the main effects of the rare variants using weighted ridge regression while adjusting for covariates. We demonstrate the performance of iSKAT using simulation studies and illustrate its application by analysis of a candidate gene sequencing study of plasma adiponectin levels.
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