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Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies

Gene-environment (GxE) interaction is one potential explanation for the missing heritability problem. A popular approach to genome-wide environment interaction studies (GWEIS) is based on regression models involving interactions between genetic variants and environment variables. Unfortunately, GWEI...

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Autores principales: Ueki, Masao, Fujii, Masahiro, Tamiya, Gen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638962/
https://www.ncbi.nlm.nih.gov/pubmed/31318927
http://dx.doi.org/10.1371/journal.pone.0219825
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author Ueki, Masao
Fujii, Masahiro
Tamiya, Gen
author_facet Ueki, Masao
Fujii, Masahiro
Tamiya, Gen
author_sort Ueki, Masao
collection PubMed
description Gene-environment (GxE) interaction is one potential explanation for the missing heritability problem. A popular approach to genome-wide environment interaction studies (GWEIS) is based on regression models involving interactions between genetic variants and environment variables. Unfortunately, GWEIS encounters systematically inflated (or deflated) test statistics more frequently than a marginal association study. The problematic behavior may occur due to poor specification of the null model (i.e. the model without genetic effect) in GWEIS. Improved null model specification may resolve the problem, but the investigation requires many time-consuming analyses of genome-wide scans, e.g. by trying out several transformations of the phenotype. It is therefore helpful if we can predict such problematic behavior beforehand. We present a simple closed-form formula to assess problematic behavior of GWEIS under the null hypothesis of no genetic effects. It requires only phenotype, environment variables, and covariates, enabling quick identification of systematic test statistic inflation or deflation. Applied to real data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), our formula identified problematic studies from among hundreds GWEIS considering each metabolite as the environment variable in GxE interaction. Our formula is useful to quickly identify problematic GWEIS without requiring a genome-wide scan.
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spelling pubmed-66389622019-07-25 Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies Ueki, Masao Fujii, Masahiro Tamiya, Gen PLoS One Research Article Gene-environment (GxE) interaction is one potential explanation for the missing heritability problem. A popular approach to genome-wide environment interaction studies (GWEIS) is based on regression models involving interactions between genetic variants and environment variables. Unfortunately, GWEIS encounters systematically inflated (or deflated) test statistics more frequently than a marginal association study. The problematic behavior may occur due to poor specification of the null model (i.e. the model without genetic effect) in GWEIS. Improved null model specification may resolve the problem, but the investigation requires many time-consuming analyses of genome-wide scans, e.g. by trying out several transformations of the phenotype. It is therefore helpful if we can predict such problematic behavior beforehand. We present a simple closed-form formula to assess problematic behavior of GWEIS under the null hypothesis of no genetic effects. It requires only phenotype, environment variables, and covariates, enabling quick identification of systematic test statistic inflation or deflation. Applied to real data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), our formula identified problematic studies from among hundreds GWEIS considering each metabolite as the environment variable in GxE interaction. Our formula is useful to quickly identify problematic GWEIS without requiring a genome-wide scan. Public Library of Science 2019-07-18 /pmc/articles/PMC6638962/ /pubmed/31318927 http://dx.doi.org/10.1371/journal.pone.0219825 Text en © 2019 Ueki et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ueki, Masao
Fujii, Masahiro
Tamiya, Gen
Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies
title Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies
title_full Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies
title_fullStr Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies
title_full_unstemmed Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies
title_short Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies
title_sort quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638962/
https://www.ncbi.nlm.nih.gov/pubmed/31318927
http://dx.doi.org/10.1371/journal.pone.0219825
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