A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes

BACKGROUND: Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. METHODS: We performed a large transcriptome-wide association study (TWAS) leveraging modif...

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Autores principales: Sun, Yanfa, Zhu, Jingjing, Zhou, Dan, Canchi, Saranya, Wu, Chong, Cox, Nancy J., Rissman, Robert A., Gamazon, Eric R., Wu, Lang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Research
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408990/
https://www.ncbi.nlm.nih.gov/pubmed/34470669
http://dx.doi.org/10.1186/s13073-021-00959-y
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author Sun, Yanfa
Zhu, Jingjing
Zhou, Dan
Canchi, Saranya
Wu, Chong
Cox, Nancy J.
Rissman, Robert A.
Gamazon, Eric R.
Wu, Lang
author_facet Sun, Yanfa
Zhu, Jingjing
Zhou, Dan
Canchi, Saranya
Wu, Chong
Cox, Nancy J.
Rissman, Robert A.
Gamazon, Eric R.
Wu, Lang
author_sort Sun, Yanfa
collection PubMed
description BACKGROUND: Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. METHODS: We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry. RESULTS: We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10(−6)). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal. CONCLUSIONS: Our study provides new insights into the etiology and underlying genetic architecture of AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00959-y.
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spelling pubmed-84089902021-09-01 A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes Sun, Yanfa Zhu, Jingjing Zhou, Dan Canchi, Saranya Wu, Chong Cox, Nancy J. Rissman, Robert A. Gamazon, Eric R. Wu, Lang Genome Med Research BACKGROUND: Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. METHODS: We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry. RESULTS: We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10(−6)). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal. CONCLUSIONS: Our study provides new insights into the etiology and underlying genetic architecture of AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00959-y. BioMed Central 2021-09-01 /pmc/articles/PMC8408990/ /pubmed/34470669 http://dx.doi.org/10.1186/s13073-021-00959-y Text en © The Author(s) 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Sun, Yanfa
Zhu, Jingjing
Zhou, Dan
Canchi, Saranya
Wu, Chong
Cox, Nancy J.
Rissman, Robert A.
Gamazon, Eric R.
Wu, Lang
A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes
title A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes
title_full A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes
title_fullStr A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes
title_full_unstemmed A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes
title_short A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes
title_sort transcriptome-wide association study of alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408990/
https://www.ncbi.nlm.nih.gov/pubmed/34470669
http://dx.doi.org/10.1186/s13073-021-00959-y
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