A characterization of cis- and trans-heritability of RNA-Seq-based gene expression

Klaasjan G. Ouwens*, Rick Jansen, Michel G. Nivard, Jenny van Dongen, Maia J. Frieser, Jouke-Jan Hottenga, Wibowo Arindrarto, Annique Claringbould, Maarten van Iterson, Hailiang Mei, Lude Franke, Bastiaan T. Heijmans, Peter A. C. 't Hoen, Joyce van Meurs, Andrew Brooks, Brenda W. J. H. Penninx, Dorret Boomsma, Aaron Isaacs, Rene Pool, Jouke J. HottengaMarleen M. J. van Greevenbroek, Coen D. A. Stehouwer, Carla J. H. van der Kallen, Casper G. Schalkwijk, Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Jan H. Veldink, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, Andre G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Michiel van Galen, Jan Bot, Dasha Zhernakova, Peter van't Hof, Patrick Deelen, Irene Nooren, Matthijs Moed, BIOS Consortium

*Corresponding author for this work

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Abstract

Insights into individual differences in gene expression and its heritability (h(2)) 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 h(total)(2), composed of cis-heritability (h(cis)(2), the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h(res)(2), the residual variance explained by all other genome-wide variants). Mean h(total)(2) was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h(2) = 0.14, p = 6.15 x 10(-258)). Mean h(cis)(2) was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, rho = 0.76, p <10(-308)) and with estimates from earlier RNA-Seq-based studies. Mean h(res)(2) was 0.20 and correlated with the beta of the corresponding trans-eQTL (rho = 0.04, p <1.89 x 10(-3)) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 x 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-h(2) estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.

Original languageEnglish
Pages (from-to)253-263
Number of pages11
JournalEuropean Journal of Human Genetics
Volume28
Issue number2
DOIs
Publication statusPublished - Feb 2020

Keywords

  • AGE

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