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Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder

Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we intro...

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Autores principales: Huang, Kunling, Wu, Yuchang, Shin, Junha, Zheng, Ye, Siahpirani, Alireza Fotuhi, Lin, Yupei, Ni, Zheng, Chen, Jiawen, You, Jing, Keles, Sunduz, Wang, Daifeng, Roy, Sushmita, Lu, Qiongshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888619/
https://www.ncbi.nlm.nih.gov/pubmed/33539344
http://dx.doi.org/10.1371/journal.pgen.1009309
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author Huang, Kunling
Wu, Yuchang
Shin, Junha
Zheng, Ye
Siahpirani, Alireza Fotuhi
Lin, Yupei
Ni, Zheng
Chen, Jiawen
You, Jing
Keles, Sunduz
Wang, Daifeng
Roy, Sushmita
Lu, Qiongshi
author_facet Huang, Kunling
Wu, Yuchang
Shin, Junha
Zheng, Ye
Siahpirani, Alireza Fotuhi
Lin, Yupei
Ni, Zheng
Chen, Jiawen
You, Jing
Keles, Sunduz
Wang, Daifeng
Roy, Sushmita
Lu, Qiongshi
author_sort Huang, Kunling
collection PubMed
description Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p = 2.1E-7), a transcription factor mainly expressed in developmental brain. Gene targets regulated by POU3F2 showed a 2.7-fold enrichment for known ASD genes (p = 2.0E-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p = 7.1E-5). These results provide a novel connection between rare and common variants, whereby ASD genes affected by very rare mutations are regulated by an unlinked transcription factor affected by common genetic variations.
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spelling pubmed-78886192021-02-23 Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder Huang, Kunling Wu, Yuchang Shin, Junha Zheng, Ye Siahpirani, Alireza Fotuhi Lin, Yupei Ni, Zheng Chen, Jiawen You, Jing Keles, Sunduz Wang, Daifeng Roy, Sushmita Lu, Qiongshi PLoS Genet Research Article Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p = 2.1E-7), a transcription factor mainly expressed in developmental brain. Gene targets regulated by POU3F2 showed a 2.7-fold enrichment for known ASD genes (p = 2.0E-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p = 7.1E-5). These results provide a novel connection between rare and common variants, whereby ASD genes affected by very rare mutations are regulated by an unlinked transcription factor affected by common genetic variations. Public Library of Science 2021-02-04 /pmc/articles/PMC7888619/ /pubmed/33539344 http://dx.doi.org/10.1371/journal.pgen.1009309 Text en © 2021 Huang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Huang, Kunling
Wu, Yuchang
Shin, Junha
Zheng, Ye
Siahpirani, Alireza Fotuhi
Lin, Yupei
Ni, Zheng
Chen, Jiawen
You, Jing
Keles, Sunduz
Wang, Daifeng
Roy, Sushmita
Lu, Qiongshi
Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
title Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
title_full Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
title_fullStr Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
title_full_unstemmed Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
title_short Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
title_sort transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888619/
https://www.ncbi.nlm.nih.gov/pubmed/33539344
http://dx.doi.org/10.1371/journal.pgen.1009309
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