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

Rene Luijk; Koen F. Dekkers; Maarten van Iterson; Wibowo Arindrarto; Annique Claringbould; Paul Hop; Dorret Boomsma; Cornelia M. van Duijn; Marleen M. J. van Greevenbroek; Jan H. Veldink; Cisca Wijmenga; Lude Franke; Peter A. C. 't Hoend; Rick Jansen; Joyce van Meurs; Hailiang Mei; P. Eline Slagboomi; Bastiaan T. Heijmans; Erik W. van Zwet; BIOS Consortium

doi:10.1038/s41467-018-05452-6

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

Rene Luijk, Koen F. Dekkers, Maarten van Iterson, Wibowo Arindrarto, Annique Claringbould, Paul Hop, Dorret Boomsma, Cornelia M. van Duijn, Marleen M. J. van Greevenbroek, Jan H. Veldink, Cisca Wijmenga, Lude Franke, Peter A. C. 't Hoend, Rick Jansen, Joyce van Meurs, Hailiang Mei, P. Eline Slagboomi, Bastiaan T. Heijmans^*, Erik W. van Zwet^*, BIOS Consortium

^*Corresponding author for this work

Interne Geneeskunde

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 x 10(-10)), among which transcription factors were over-represented (Fisher's P = 3.3 x 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.

Original language	English
Article number	3097
Number of pages	10
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-05452-6
Publication status	Published - 6 Aug 2018

Keywords

MENDELIAN RANDOMIZATION
TRANSCRIPTIONAL REGULATION
ENDOGENOUS RETROVIRUSES
INSULIN-SECRETION
HUMAN TISSUES
TRANS-EQTLS
SAMPLE-SIZE
CELL-DEATH
RNA-SEQ
ASSOCIATION
APOPTOSIS
HAIR
ZAC1
EXPRESSION

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Luijk, R., Dekkers, K. F., van Iterson, M., Arindrarto, W., Claringbould, A., Hop, P., Boomsma, D., van Duijn, C. M., van Greevenbroek, M. M. J., Veldink, J. H., Wijmenga, C., Franke, L., 't Hoend, P. A. C., Jansen, R., van Meurs, J., Mei, H., Slagboomi, P. E., Heijmans, B. T., van Zwet, E. W., & BIOS Consortium (2018). Genome-wide identification of directed gene networks using large-scale population genomics data. Nature Communications, 9, Article 3097. https://doi.org/10.1038/s41467-018-05452-6

@article{2dd4de12ff274d90ba83836039c5e6c6,

title = "Genome-wide identification of directed gene networks using large-scale population genomics data",

abstract = "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 x 10(-10)), among which transcription factors were over-represented (Fisher's P = 3.3 x 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.",

keywords = "MENDELIAN RANDOMIZATION, TRANSCRIPTIONAL REGULATION, ENDOGENOUS RETROVIRUSES, INSULIN-SECRETION, HUMAN TISSUES, TRANS-EQTLS, SAMPLE-SIZE, CELL-DEATH, RNA-SEQ, ASSOCIATION, APOPTOSIS, HAIR, ZAC1, EXPRESSION",

author = "Rene Luijk and Dekkers, {Koen F.} and {van Iterson}, Maarten and Wibowo Arindrarto and Annique Claringbould and Paul Hop and Dorret Boomsma and {van Duijn}, {Cornelia M.} and {van Greevenbroek}, {Marleen M. J.} and Veldink, {Jan H.} and Cisca Wijmenga and Lude Franke and {'t Hoend}, {Peter A. C.} and Rick Jansen and {van Meurs}, Joyce and Hailiang Mei and Slagboomi, {P. Eline} and Heijmans, {Bastiaan T.} and {van Zwet}, {Erik W.} and {BIOS Consortium}",

year = "2018",

month = aug,

day = "6",

doi = "10.1038/s41467-018-05452-6",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Luijk, R, Dekkers, KF, van Iterson, M, Arindrarto, W, Claringbould, A, Hop, P, Boomsma, D, van Duijn, CM, van Greevenbroek, MMJ, Veldink, JH, Wijmenga, C, Franke, L, 't Hoend, PAC, Jansen, R, van Meurs, J, Mei, H, Slagboomi, PE, Heijmans, BT, van Zwet, EW & BIOS Consortium 2018, 'Genome-wide identification of directed gene networks using large-scale population genomics data', Nature Communications, vol. 9, 3097. https://doi.org/10.1038/s41467-018-05452-6

TY - JOUR

T1 - Genome-wide identification of directed gene networks using large-scale population genomics data

AU - Luijk, Rene

AU - Dekkers, Koen F.

AU - van Iterson, Maarten

AU - Arindrarto, Wibowo

AU - Claringbould, Annique

AU - Hop, Paul

AU - Boomsma, Dorret

AU - van Duijn, Cornelia M.

AU - van Greevenbroek, Marleen M. J.

AU - Veldink, Jan H.

AU - Wijmenga, Cisca

AU - Franke, Lude

AU - 't Hoend, Peter A. C.

AU - Jansen, Rick

AU - van Meurs, Joyce

AU - Mei, Hailiang

AU - Slagboomi, P. Eline

AU - Heijmans, Bastiaan T.

AU - van Zwet, Erik W.

AU - BIOS Consortium

PY - 2018/8/6

Y1 - 2018/8/6

N2 - 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 x 10(-10)), among which transcription factors were over-represented (Fisher's P = 3.3 x 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.

AB - 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 x 10(-10)), among which transcription factors were over-represented (Fisher's P = 3.3 x 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.

KW - MENDELIAN RANDOMIZATION

KW - TRANSCRIPTIONAL REGULATION

KW - ENDOGENOUS RETROVIRUSES

KW - INSULIN-SECRETION

KW - HUMAN TISSUES

KW - TRANS-EQTLS

KW - SAMPLE-SIZE

KW - CELL-DEATH

KW - RNA-SEQ

KW - ASSOCIATION

KW - APOPTOSIS

KW - HAIR

KW - ZAC1

KW - EXPRESSION

U2 - 10.1038/s41467-018-05452-6

DO - 10.1038/s41467-018-05452-6

M3 - Article

C2 - 30082726

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 3097

ER -