Journal Article

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

Deelen Joris, Veldink, Jan H, Hottenga, Jouke J, Brooks, Andrew I, van Iterson Maarten, Kielbasa, Szymon M, Verkerk Marijn, Penninx Brenda W J H, Zhernakova Sasha, Wijmenga Cisca, Swertz, Morris A, Jouke-Jan, Hottenga, van der Kallen Carla J H, Jansen, Rick, Luijk René, Isaacs, Aaron, van Greevenbroek Marleen M J, van Dijk Freerk, Frieser Maia J, Beekman, Marian, Deelen Patrick, Wibowo, Arindrarto, Eline, Slagboom P, Pool René, van den Berg Leonard H, van Zwet Erik W, van Duijn Cornelia M, Uitterlinden, André G, van Galen Michiel, Zhernakova Dasha V, Annique, Claringbould, Stehouwer Coen D A, Mila, Jhamai P, Tigchelaar, Ettje F, Diana, van Heemst, van der Breggen Ruud, van Dongen Jenny, A C ’t Hoen Peter, Verbiest, Michael, van Rooij Jeroen, Franke Lude, Boomsma Dorret I, Jan Bonder Marc, t Hoen Peter-Bram, Ouwens, Klaasjan G, Hofman, Bert A, Nivard, Michel G, Mei Hailiang, Lakenberg Nico, Heijmans, Bastiaan T, Bot, Jan, Nooren Irene, Suchiman H Eka D, van’t Hof Peter, Schalkwijk, Casper G, Moed Matthijs, Vermaat Martijn, van Meurs Joyce

2020

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Cytokines / DNA microarrays / Gene expression / Genome-wide association studies / Genomes / Heritability / Immune system / Phenotypes / Ribonucleic acid / RNA / Single-nucleotide polymorphism