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

H. Eka D. Suchiman, Jouke J. Hottenga, René Pool, Dorret I. Boomsma, BIOS (Biobank-based Integrative Omics Study) Consortium

Research output: Contribution to JournalArticleAcademicpeer-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 × 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.

Original languageEnglish
Article number3097
Pages (from-to)1-10
Number of pages10
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 6 Aug 2018

Funding

This research was financially supported by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO, numbers 184.021.007 and 184.033.111). Samples were contributed by LifeLines, the Leiden Longevity Study, the Netherlands Twin Registry (NTR), the Rotterdam Study, the Genetic Research in Isolated Populations program, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study and the Prospective ALS study Netherlands (PAN). We thank the participants of all afore-mentioned biobanks and acknowledge the contributions of the investigators to this study. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. We acknowledge the support from the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project Generating the best evidence-based pharmaceutical targets for atherosclerosis (CVON2011-19).

FundersFunder number
BBMRI-NL
Dutch Heart Foundation
Dutch Government
Netherlands CardioVascular Research Initiative
Royal Netherlands Academy of SciencesCVON2011-19
ZonMw
Nederlandse Organisatie voor Wetenschappelijk Onderzoek184.033.111, 184.021.007
Nederlandse Federatie van Universitair Medische Centra

    Cohort Studies

    • Netherlands Twin Register (NTR)

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