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Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection

Recent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here, we in...

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Autores principales: Novo, Irene, López-Cortegano, Eugenio, Caballero, Armando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338839/
https://www.ncbi.nlm.nih.gov/pubmed/34228221
http://dx.doi.org/10.1007/s00439-021-02308-w
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author Novo, Irene
López-Cortegano, Eugenio
Caballero, Armando
author_facet Novo, Irene
López-Cortegano, Eugenio
Caballero, Armando
author_sort Novo, Irene
collection PubMed
description Recent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here, we investigate the mean frequency, effect size and recombination rate associated with pleiotropic variants, and focus particularly on whether highly pleiotropic variants are enriched in regions with putative strong background selection. We evaluate variants for 41 human traits using data from the NHGRI-EBI GWAS Catalog, as well as data from other three studies. Our results show that variants involving a higher degree of pleiotropy tend to be more common, have larger mean effect sizes, and contribute more to heritability than variants with a lower degree of pleiotropy. This is consistent with the fact that variants of large effect and frequency are more likely detected by GWAS. Using data from four different studies, we also show that more pleiotropic variants are enriched in genome regions with stronger background selection than less pleiotropic variants, suggesting that highly pleiotropic variants are subjected to strong purifying selection. From the above results, we hypothesized that a number of highly pleiotropic variants of low effect/frequency may pass undetected by GWAS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-021-02308-w.
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spelling pubmed-83388392021-08-20 Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection Novo, Irene López-Cortegano, Eugenio Caballero, Armando Hum Genet Original Investigation Recent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here, we investigate the mean frequency, effect size and recombination rate associated with pleiotropic variants, and focus particularly on whether highly pleiotropic variants are enriched in regions with putative strong background selection. We evaluate variants for 41 human traits using data from the NHGRI-EBI GWAS Catalog, as well as data from other three studies. Our results show that variants involving a higher degree of pleiotropy tend to be more common, have larger mean effect sizes, and contribute more to heritability than variants with a lower degree of pleiotropy. This is consistent with the fact that variants of large effect and frequency are more likely detected by GWAS. Using data from four different studies, we also show that more pleiotropic variants are enriched in genome regions with stronger background selection than less pleiotropic variants, suggesting that highly pleiotropic variants are subjected to strong purifying selection. From the above results, we hypothesized that a number of highly pleiotropic variants of low effect/frequency may pass undetected by GWAS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-021-02308-w. Springer Berlin Heidelberg 2021-07-06 2021 /pmc/articles/PMC8338839/ /pubmed/34228221 http://dx.doi.org/10.1007/s00439-021-02308-w Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Investigation
Novo, Irene
López-Cortegano, Eugenio
Caballero, Armando
Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection
title Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection
title_full Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection
title_fullStr Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection
title_full_unstemmed Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection
title_short Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection
title_sort highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338839/
https://www.ncbi.nlm.nih.gov/pubmed/34228221
http://dx.doi.org/10.1007/s00439-021-02308-w
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