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Test for rare variants by environment interactions in sequencing association studies.

ABSTRACT: 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.

SUBMITTER: Lin X

PROVIDER: S-EPMC4733434 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Test for rare variants by environment interactions in sequencing association studies.

Lin Xinyi X Lee Seunggeun S Wu Michael C MC Wang Chaolong C Chen Han H Li Zilin Z Lin Xihong X

Biometrics 20150730 1

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 ...[more]

PMID: 26229047

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Project description:Genetic association analyses of rare variants in next-generation sequencing (NGS) studies are fundamentally challenging due to the presence of a very large number of candidate variants at extremely low minor allele frequencies. Recent developments often focus on pooling multiple variants to provide association analysis at the gene instead of the locus level. Nonetheless, pinpointing individual variants is a critical goal for genomic researches as such information can facilitate the precise delineation of molecular mechanisms and functions of genetic factors on diseases. Due to the extreme rarity of mutations and high-dimensionality, significances of causal variants cannot easily stand out from those of noncausal ones. Consequently, standard false-positive control procedures, such as the Bonferroni and false discovery rate (FDR), are often impractical to apply, as a majority of the causal variants can only be identified along with a few but unknown number of noncausal variants. To provide informative analysis of individual variants in large-scale sequencing studies, we propose the Adaptive False-Negative Control (AFNC) procedure that can include a large proportion of causal variants with high confidence by introducing a novel statistical inquiry to determine those variants that can be confidently dispatched as noncausal. The AFNC provides a general framework that can accommodate for a variety of models and significance tests. The procedure is computationally efficient and can adapt to the underlying proportion of causal variants and quality of significance rankings. Extensive simulation studies across a plethora of scenarios demonstrate that the AFNC is advantageous for identifying individual rare variants, whereas the Bonferroni and FDR are exceedingly over-conservative for rare variants association studies. In the analyses of the CoLaus dataset, AFNC has identified individual variants most responsible for gene-level significances. Moreover, single-variant results using the AFNC have been successfully applied to infer related genes with annotation information.

Dataset Information

Test for rare variants by environment interactions in sequencing association studies.

Publications

Test for rare variants by environment interactions in sequencing association studies.

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