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

Mostra el registre complet Registre parcial de l'ítem

  • dc.contributor.author Guindo Martínez, Marta
  • dc.contributor.author Bonàs-Guarch, Silvia
  • dc.contributor.author Miguel Escalada, Irene
  • dc.contributor.author Torrents, David
  • dc.date.accessioned 2021-11-24T07:40:31Z
  • dc.date.available 2021-11-24T07:40:31Z
  • dc.date.issued 2021
  • dc.description.abstract 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.
  • dc.description.sponsorship 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).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Guindo-Martínez M, Amela R, Bonàs-Guarch S, Puiggròs M, Salvoro C, Miguel-Escalada I et al. The impact of non-additive genetic associations on age-related complex diseases. Nat Commun. 2021;12(1):2436. DOI: 10.1038/s41467-021-21952-4
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-021-21952-4
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/49044
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2021;12(1):2436
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/754433
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BES-2016-076791
  • dc.rights © 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/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Genetic predisposition to disease
  • dc.subject.keyword Genome-wide association studies
  • dc.title The impact of non-additive genetic associations on age-related complex diseases
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)