The impact of non-additive genetic associations on age-related complex diseases

Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation...

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Autores: Guindo Martínez, Marta, Bonàs-Guarch, Silvia, Miguel Escalada, Irene, Torrents, David
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/49044
Acceso en línea:http://hdl.handle.net/10230/49044
http://dx.doi.org/10.1038/s41467-021-21952-4
Access Level:acceso abierto
Palabra clave:Genetic predisposition to disease
Genome-wide association studies
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spelling The impact of non-additive genetic associations on age-related complex diseasesGuindo Martínez, MartaBonàs-Guarch, SilviaMiguel Escalada, IreneTorrents, DavidGenetic predisposition to diseaseGenome-wide association studiesGenome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases.This work has been sponsored by the grant SEV-2011-00067 and SEV2015-0493 of Severo Ochoa Program, awarded by the Spanish Government, by the grant TIN2015-65316-P, awarded by the Spanish Ministry of Science and Innovation, and by the Generalitat de Catalunya (contract 2014-SGR-1051). This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by a Sara Borrell Fellowship from the Instituto Carlos III, Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR) and by the American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068. Sílvia Bonàs was supported by FI-DGR Fellowship from FIDGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya), and a ‘Juan de la Cierva’ postdoctoral fellowship (MINECO;FJCI-2017-32090). Cecilia Salvoro received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement H2020-MSCA-COFUND-2016-754433. Cristian Ramon-Cortes pre-doctoral contract is financed by the Spanish Ministry of Science, Innovation, and Universities under contract BES-2016-076791. Elizabeth G. Atkinson was supported by the National Institutes of Mental Health (grants K01MH121659 and T32MH017119).Nature Research202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/49044http://dx.doi.org/10.1038/s41467-021-21952-4reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésNat Commun. 2021;12(1):2436info:eu-repo/grantAgreement/EC/H2020/754433info:eu-repo/grantAgreement/ES/1PE/BES-2016-076791© The Author(s) 2021. Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/490442026-06-12T07:21:37Z
dc.title.none.fl_str_mv The impact of non-additive genetic associations on age-related complex diseases
title The impact of non-additive genetic associations on age-related complex diseases
spellingShingle The impact of non-additive genetic associations on age-related complex diseases
Guindo Martínez, Marta
Genetic predisposition to disease
Genome-wide association studies
title_short The impact of non-additive genetic associations on age-related complex diseases
title_full The impact of non-additive genetic associations on age-related complex diseases
title_fullStr The impact of non-additive genetic associations on age-related complex diseases
title_full_unstemmed The impact of non-additive genetic associations on age-related complex diseases
title_sort The impact of non-additive genetic associations on age-related complex diseases
dc.creator.none.fl_str_mv Guindo Martínez, Marta
Bonàs-Guarch, Silvia
Miguel Escalada, Irene
Torrents, David
author Guindo Martínez, Marta
author_facet Guindo Martínez, Marta
Bonàs-Guarch, Silvia
Miguel Escalada, Irene
Torrents, David
author_role author
author2 Bonàs-Guarch, Silvia
Miguel Escalada, Irene
Torrents, David
author2_role author
author
author
dc.subject.none.fl_str_mv Genetic predisposition to disease
Genome-wide association studies
topic Genetic predisposition to disease
Genome-wide association studies
description Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/49044
http://dx.doi.org/10.1038/s41467-021-21952-4
url http://hdl.handle.net/10230/49044
http://dx.doi.org/10.1038/s41467-021-21952-4
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nat Commun. 2021;12(1):2436
info:eu-repo/grantAgreement/EC/H2020/754433
info:eu-repo/grantAgreement/ES/1PE/BES-2016-076791
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
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repository.mail.fl_str_mv
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