Abstract
Insights into individual differences in gene expression and its heritability (h2) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h2total, composed of cis-heritability (h2cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2res, the residual variance explained by all other genome-wide variants). Mean h2total was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h2 = 0.14, p = 6.15 × 10−258). Mean h2cis was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, ρ = 0.76, p < 10−308) and with estimates from earlier RNA-Seq-based studies. Mean h2res was 0.20 and correlated with the beta of the corresponding trans-eQTL (ρ = 0.04, p < 1.89 × 10−3) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 × 10−15), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h2 estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.
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Acknowledgements
We very warmly thank all participants in the study. This study makes use of data in the Netherlands Twin Register with prof. D.I. Boomsma as principle investigator.
Funding
This work was performed within the framework of the BBMRI - NL Consortium, a research infrastructure financed by the Dutch government (NWO, nos. 184.021.007 and 184.033.111). Genotyping was made possible by grants from NWO/SPI 56-464-14192, Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995) and European Research Council (ERC-230374). DIB acknowledges her KNAW Academy Professor Award (PAH/6635).
BIOS Consortium
Bastiaan T. Heijmans12, Peter A. C. ’t Hoen13, Joyce van Meurs14, Aaron Isaacs15, Rick Jansen16, Lude Franke17, Dorret I. Boomsma18, René Pool18, Jenny van Dongen18, Jouke J. Hottenga18, Marleen M. J. van Greevenbroek19, Coen D. A. Stehouwer19, Carla J. H. van der Kallen19, Casper G. Schalkwijk19, Cisca Wijmenga17, Lude Franke17, Sasha Zhernakova17, Ettje F. Tigchelaar17, P. Eline Slagboom12, Marian Beekman12, Joris Deelen12, Diana van Heemst20, Jan H. Veldink21, Leonard H. van den Berg21, Cornelia M. van Duijn15, Bert A. Hofman22, Aaron Isaacs15, André G. Uitterlinden14, Joyce van Meurs14, P. Mila Jhamai14, Michael Verbiest14, H. Eka D. Suchiman12, Marijn Verkerk14, Ruud van der Breggen12, Jeroen van Rooij14, Nico Lakenberg12, Hailiang Mei23, Maarten van Iterson12, Michiel van Galen13, Jan Bot24, Dasha V. Zhernakova17, Rick Jansen16, Peter van’t Hof23, Patrick Deelen17, Irene Nooren24, Peter A. C. ’t Hoen13, Bastiaan T. Heijmans12, Matthijs Moed12, Lude Franke17, Martijn Vermaat14, Dasha V. Zhernakova17, René Luijk12, Marc Jan Bonder17, Maarten van Iterson12, Patrick Deelen17, Freerk van Dijk25, Michiel van Galen13, Wibowo Arindrarto23, Szymon M. Kielbasa26, Morris A. Swertz25, Erik. W van Zwet26, Rick Jansen16, Peter-Bram ’t Hoen13, Bastiaan T. Heijmans12
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The NTR study was approved by the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Center, Amsterdam (institutional review board [IRB] number IRB-2991 under Federal wide Assurance 3703; IRB/institute code NTR 03-180). All participants provided written informed consent.
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Ouwens, K.G., Jansen, R., Nivard, M.G. et al. A characterization of cis- and trans-heritability of RNA-Seq-based gene expression. Eur J Hum Genet 28, 253–263 (2020). https://doi.org/10.1038/s41431-019-0511-5
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DOI: https://doi.org/10.1038/s41431-019-0511-5
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