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Review and further developments in statistical corrections for Winner’s Curse in genetic association studies
Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replic...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10538662/ https://www.ncbi.nlm.nih.gov/pubmed/37721937 http://dx.doi.org/10.1371/journal.pgen.1010546 |
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author | Forde, Amanda Hemani, Gibran Ferguson, John |
author_facet | Forde, Amanda Hemani, Gibran Ferguson, John |
author_sort | Forde, Amanda |
collection | PubMed |
description | Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known as Winner’s Curse is responsible for this upward bias present in association estimates of significant variants in the discovery study. We review existing Winner’s Curse correction methods which require only GWAS summary statistics in order to make adjustments. In addition, we propose modifications to improve existing methods and propose a novel approach which uses the parametric bootstrap. We evaluate and compare methods, first using a wide variety of simulated data sets and then, using real data sets for three different traits. The metric, estimated mean squared error (MSE) over significant SNPs, was primarily used for method assessment. Our results indicate that widely used conditional likelihood based methods tend to perform poorly. The other considered methods behave much more similarly, with our proposed bootstrap method demonstrating very competitive performance. To complement this review, we have developed an R package, ‘winnerscurse’ which can be used to implement these various Winner’s Curse adjustment methods to GWAS summary statistics. |
format | Online Article Text |
id | pubmed-10538662 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-105386622023-09-29 Review and further developments in statistical corrections for Winner’s Curse in genetic association studies Forde, Amanda Hemani, Gibran Ferguson, John PLoS Genet Research Article Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known as Winner’s Curse is responsible for this upward bias present in association estimates of significant variants in the discovery study. We review existing Winner’s Curse correction methods which require only GWAS summary statistics in order to make adjustments. In addition, we propose modifications to improve existing methods and propose a novel approach which uses the parametric bootstrap. We evaluate and compare methods, first using a wide variety of simulated data sets and then, using real data sets for three different traits. The metric, estimated mean squared error (MSE) over significant SNPs, was primarily used for method assessment. Our results indicate that widely used conditional likelihood based methods tend to perform poorly. The other considered methods behave much more similarly, with our proposed bootstrap method demonstrating very competitive performance. To complement this review, we have developed an R package, ‘winnerscurse’ which can be used to implement these various Winner’s Curse adjustment methods to GWAS summary statistics. Public Library of Science 2023-09-18 /pmc/articles/PMC10538662/ /pubmed/37721937 http://dx.doi.org/10.1371/journal.pgen.1010546 Text en © 2023 Forde et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://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 Forde, Amanda Hemani, Gibran Ferguson, John Review and further developments in statistical corrections for Winner’s Curse in genetic association studies |
title | Review and further developments in statistical corrections for Winner’s Curse in genetic association studies |
title_full | Review and further developments in statistical corrections for Winner’s Curse in genetic association studies |
title_fullStr | Review and further developments in statistical corrections for Winner’s Curse in genetic association studies |
title_full_unstemmed | Review and further developments in statistical corrections for Winner’s Curse in genetic association studies |
title_short | Review and further developments in statistical corrections for Winner’s Curse in genetic association studies |
title_sort | review and further developments in statistical corrections for winner’s curse in genetic association studies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10538662/ https://www.ncbi.nlm.nih.gov/pubmed/37721937 http://dx.doi.org/10.1371/journal.pgen.1010546 |
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