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The Effect of Population Structure on Murine Genome-Wide Association Studies

The ability to use genome-wide association studies (GWAS) for genetic discovery depends upon our ability to distinguish true causative from false positive association signals. Population structure (PS) has been shown to cause false positive signals in GWAS. PS correction is routinely used for analys...

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Autores principales: Wang, Meiyue, Fang, Zhuoqing, Yoo, Boyoung, Bejerano, Gill, Peltz, Gary
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475632/
https://www.ncbi.nlm.nih.gov/pubmed/34589118
http://dx.doi.org/10.3389/fgene.2021.745361
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author Wang, Meiyue
Fang, Zhuoqing
Yoo, Boyoung
Bejerano, Gill
Peltz, Gary
author_facet Wang, Meiyue
Fang, Zhuoqing
Yoo, Boyoung
Bejerano, Gill
Peltz, Gary
author_sort Wang, Meiyue
collection PubMed
description The ability to use genome-wide association studies (GWAS) for genetic discovery depends upon our ability to distinguish true causative from false positive association signals. Population structure (PS) has been shown to cause false positive signals in GWAS. PS correction is routinely used for analysis of human GWAS results, and it has been assumed that it also should be utilized for murine GWAS using inbred strains. Nevertheless, there are fundamental differences between murine and human GWAS, and the impact of PS on murine GWAS results has not been carefully investigated. To assess the impact of PS on murine GWAS, we examined 8223 datasets that characterized biomedical responses in panels of inbred mouse strains. Rather than treat PS as a confounding variable, we examined it as a response variable. Surprisingly, we found that PS had a minimal impact on datasets measuring responses in ≤20 strains; and had surprisingly little impact on most datasets characterizing 21 – 40 inbred strains. Moreover, we show that true positive association signals arising from haplotype blocks, SNPs or indels, which were experimentally demonstrated to be causative for trait differences, would be rejected if PS correction were applied to them. Our results indicate because of the special conditions created by GWAS (the use of inbred strains, small sample sizes) PS assessment results should be carefully evaluated in conjunction with other criteria, when murine GWAS results are evaluated.
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spelling pubmed-84756322021-09-28 The Effect of Population Structure on Murine Genome-Wide Association Studies Wang, Meiyue Fang, Zhuoqing Yoo, Boyoung Bejerano, Gill Peltz, Gary Front Genet Genetics The ability to use genome-wide association studies (GWAS) for genetic discovery depends upon our ability to distinguish true causative from false positive association signals. Population structure (PS) has been shown to cause false positive signals in GWAS. PS correction is routinely used for analysis of human GWAS results, and it has been assumed that it also should be utilized for murine GWAS using inbred strains. Nevertheless, there are fundamental differences between murine and human GWAS, and the impact of PS on murine GWAS results has not been carefully investigated. To assess the impact of PS on murine GWAS, we examined 8223 datasets that characterized biomedical responses in panels of inbred mouse strains. Rather than treat PS as a confounding variable, we examined it as a response variable. Surprisingly, we found that PS had a minimal impact on datasets measuring responses in ≤20 strains; and had surprisingly little impact on most datasets characterizing 21 – 40 inbred strains. Moreover, we show that true positive association signals arising from haplotype blocks, SNPs or indels, which were experimentally demonstrated to be causative for trait differences, would be rejected if PS correction were applied to them. Our results indicate because of the special conditions created by GWAS (the use of inbred strains, small sample sizes) PS assessment results should be carefully evaluated in conjunction with other criteria, when murine GWAS results are evaluated. Frontiers Media S.A. 2021-09-13 /pmc/articles/PMC8475632/ /pubmed/34589118 http://dx.doi.org/10.3389/fgene.2021.745361 Text en Copyright © 2021 Wang, Fang, Yoo, Bejerano and Peltz. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Wang, Meiyue
Fang, Zhuoqing
Yoo, Boyoung
Bejerano, Gill
Peltz, Gary
The Effect of Population Structure on Murine Genome-Wide Association Studies
title The Effect of Population Structure on Murine Genome-Wide Association Studies
title_full The Effect of Population Structure on Murine Genome-Wide Association Studies
title_fullStr The Effect of Population Structure on Murine Genome-Wide Association Studies
title_full_unstemmed The Effect of Population Structure on Murine Genome-Wide Association Studies
title_short The Effect of Population Structure on Murine Genome-Wide Association Studies
title_sort effect of population structure on murine genome-wide association studies
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475632/
https://www.ncbi.nlm.nih.gov/pubmed/34589118
http://dx.doi.org/10.3389/fgene.2021.745361
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