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Genome-wide identification of directed gene networks using large-scale population genomics data

Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene–gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal an...

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Autores principales: Luijk, René, Dekkers, Koen F., van Iterson, Maarten, Arindrarto, Wibowo, Claringbould, Annique, Hop, Paul, Boomsma, Dorret I., van Duijn, Cornelia M., van Greevenbroek, Marleen M. J., Veldink, Jan H., Wijmenga, Cisca, Franke, Lude, ’t Hoen, Peter A. C., Jansen, Rick, van Meurs, Joyce, Mei, Hailiang, Slagboom, P. Eline, Heijmans, Bastiaan T., van Zwet, Erik W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079029/
https://www.ncbi.nlm.nih.gov/pubmed/30082726
http://dx.doi.org/10.1038/s41467-018-05452-6
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author Luijk, René
Dekkers, Koen F.
van Iterson, Maarten
Arindrarto, Wibowo
Claringbould, Annique
Hop, Paul
Boomsma, Dorret I.
van Duijn, Cornelia M.
van Greevenbroek, Marleen M. J.
Veldink, Jan H.
Wijmenga, Cisca
Franke, Lude
’t Hoen, Peter A. C.
Jansen, Rick
van Meurs, Joyce
Mei, Hailiang
Slagboom, P. Eline
Heijmans, Bastiaan T.
van Zwet, Erik W.
author_facet Luijk, René
Dekkers, Koen F.
van Iterson, Maarten
Arindrarto, Wibowo
Claringbould, Annique
Hop, Paul
Boomsma, Dorret I.
van Duijn, Cornelia M.
van Greevenbroek, Marleen M. J.
Veldink, Jan H.
Wijmenga, Cisca
Franke, Lude
’t Hoen, Peter A. C.
Jansen, Rick
van Meurs, Joyce
Mei, Hailiang
Slagboom, P. Eline
Heijmans, Bastiaan T.
van Zwet, Erik W.
author_sort Luijk, René
collection PubMed
description Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene–gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal anchors, akin to Mendelian Randomization) and specific (by controlling for linkage disequilibrium and pleiotropy). Analysis of genotype and whole-blood RNA-sequencing data from 3072 individuals identified 49 genes as drivers of downstream transcriptional changes (Wald P < 7 × 10(−10)), among which transcription factors were overrepresented (Fisher’s P = 3.3 × 10(−7)). Our analysis suggests new gene functions and targets, including for SENP7 (zinc-finger genes involved in retroviral repression) and BCL2A1 (target genes possibly involved in auditory dysfunction). Our work highlights the utility of population genomics data in deriving directed gene expression networks. A resource of trans-effects for all 6600 genes with a genetic instrument can be explored individually using a web-based browser.
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spelling pubmed-60790292018-08-08 Genome-wide identification of directed gene networks using large-scale population genomics data Luijk, René Dekkers, Koen F. van Iterson, Maarten Arindrarto, Wibowo Claringbould, Annique Hop, Paul Boomsma, Dorret I. van Duijn, Cornelia M. van Greevenbroek, Marleen M. J. Veldink, Jan H. Wijmenga, Cisca Franke, Lude ’t Hoen, Peter A. C. Jansen, Rick van Meurs, Joyce Mei, Hailiang Slagboom, P. Eline Heijmans, Bastiaan T. van Zwet, Erik W. Nat Commun Article Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene–gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal anchors, akin to Mendelian Randomization) and specific (by controlling for linkage disequilibrium and pleiotropy). Analysis of genotype and whole-blood RNA-sequencing data from 3072 individuals identified 49 genes as drivers of downstream transcriptional changes (Wald P < 7 × 10(−10)), among which transcription factors were overrepresented (Fisher’s P = 3.3 × 10(−7)). Our analysis suggests new gene functions and targets, including for SENP7 (zinc-finger genes involved in retroviral repression) and BCL2A1 (target genes possibly involved in auditory dysfunction). Our work highlights the utility of population genomics data in deriving directed gene expression networks. A resource of trans-effects for all 6600 genes with a genetic instrument can be explored individually using a web-based browser. Nature Publishing Group UK 2018-08-06 /pmc/articles/PMC6079029/ /pubmed/30082726 http://dx.doi.org/10.1038/s41467-018-05452-6 Text en © The Author(s) 2018 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/.
spellingShingle Article
Luijk, René
Dekkers, Koen F.
van Iterson, Maarten
Arindrarto, Wibowo
Claringbould, Annique
Hop, Paul
Boomsma, Dorret I.
van Duijn, Cornelia M.
van Greevenbroek, Marleen M. J.
Veldink, Jan H.
Wijmenga, Cisca
Franke, Lude
’t Hoen, Peter A. C.
Jansen, Rick
van Meurs, Joyce
Mei, Hailiang
Slagboom, P. Eline
Heijmans, Bastiaan T.
van Zwet, Erik W.
Genome-wide identification of directed gene networks using large-scale population genomics data
title Genome-wide identification of directed gene networks using large-scale population genomics data
title_full Genome-wide identification of directed gene networks using large-scale population genomics data
title_fullStr Genome-wide identification of directed gene networks using large-scale population genomics data
title_full_unstemmed Genome-wide identification of directed gene networks using large-scale population genomics data
title_short Genome-wide identification of directed gene networks using large-scale population genomics data
title_sort genome-wide identification of directed gene networks using large-scale population genomics data
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079029/
https://www.ncbi.nlm.nih.gov/pubmed/30082726
http://dx.doi.org/10.1038/s41467-018-05452-6
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