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Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits
In genetic association studies of rare variants, low statistical power and potential violations of established estimator properties are among the main challenges of association tests. Multi-marker tests (MMTs) have been proposed to target these challenges, but any comparison with single-marker tests...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451057/ https://www.ncbi.nlm.nih.gov/pubmed/28562689 http://dx.doi.org/10.1371/journal.pone.0178504 |
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author | Konigorski, Stefan Yilmaz, Yildiz E. Pischon, Tobias |
author_facet | Konigorski, Stefan Yilmaz, Yildiz E. Pischon, Tobias |
author_sort | Konigorski, Stefan |
collection | PubMed |
description | In genetic association studies of rare variants, low statistical power and potential violations of established estimator properties are among the main challenges of association tests. Multi-marker tests (MMTs) have been proposed to target these challenges, but any comparison with single-marker tests (SMTs) has to consider that their aim is to identify causal genomic regions instead of variants. Valid power comparisons have been performed for the analysis of binary traits indicating that MMTs have higher power, but there is a lack of conclusive studies for quantitative traits. The aim of our study was therefore to fairly compare SMTs and MMTs in their empirical power to identify the same causal loci associated with a quantitative trait. The results of extensive simulation studies indicate that previous results for binary traits cannot be generalized. First, we show that for the analysis of quantitative traits, conventional estimation methods and test statistics of single-marker approaches have valid properties yielding association tests with valid type I error, even when investigating singletons or doubletons. Furthermore, SMTs lead to more powerful association tests for identifying causal genes than MMTs when the effect sizes of causal variants are large, and less powerful tests when causal variants have small effect sizes. For moderate effect sizes, whether SMTs or MMTs have higher power depends on the sample size and percentage of causal SNVs. For a more complete picture, we also compare the power in studies of quantitative and binary traits, and the power to identify causal genes with the power to identify causal rare variants. In a genetic association analysis of systolic blood pressure in the Genetic Analysis Workshop 19 data, SMTs yielded smaller p-values compared to MMTs for most of the investigated blood pressure genes, and were least influenced by the definition of gene regions. |
format | Online Article Text |
id | pubmed-5451057 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54510572017-06-12 Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits Konigorski, Stefan Yilmaz, Yildiz E. Pischon, Tobias PLoS One Research Article In genetic association studies of rare variants, low statistical power and potential violations of established estimator properties are among the main challenges of association tests. Multi-marker tests (MMTs) have been proposed to target these challenges, but any comparison with single-marker tests (SMTs) has to consider that their aim is to identify causal genomic regions instead of variants. Valid power comparisons have been performed for the analysis of binary traits indicating that MMTs have higher power, but there is a lack of conclusive studies for quantitative traits. The aim of our study was therefore to fairly compare SMTs and MMTs in their empirical power to identify the same causal loci associated with a quantitative trait. The results of extensive simulation studies indicate that previous results for binary traits cannot be generalized. First, we show that for the analysis of quantitative traits, conventional estimation methods and test statistics of single-marker approaches have valid properties yielding association tests with valid type I error, even when investigating singletons or doubletons. Furthermore, SMTs lead to more powerful association tests for identifying causal genes than MMTs when the effect sizes of causal variants are large, and less powerful tests when causal variants have small effect sizes. For moderate effect sizes, whether SMTs or MMTs have higher power depends on the sample size and percentage of causal SNVs. For a more complete picture, we also compare the power in studies of quantitative and binary traits, and the power to identify causal genes with the power to identify causal rare variants. In a genetic association analysis of systolic blood pressure in the Genetic Analysis Workshop 19 data, SMTs yielded smaller p-values compared to MMTs for most of the investigated blood pressure genes, and were least influenced by the definition of gene regions. Public Library of Science 2017-05-31 /pmc/articles/PMC5451057/ /pubmed/28562689 http://dx.doi.org/10.1371/journal.pone.0178504 Text en © 2017 Konigorski 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 Konigorski, Stefan Yilmaz, Yildiz E. Pischon, Tobias Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits |
title | Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits |
title_full | Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits |
title_fullStr | Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits |
title_full_unstemmed | Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits |
title_short | Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits |
title_sort | comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451057/ https://www.ncbi.nlm.nih.gov/pubmed/28562689 http://dx.doi.org/10.1371/journal.pone.0178504 |
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