TY - JOUR
T1 - A characterization of cis- and trans-heritability of RNA-Seq-based gene expression
AU - Ouwens, Klaasjan G.
AU - Jansen, Rick
AU - Nivard, Michel G.
AU - van Dongen, Jenny
AU - Frieser, Maia J.
AU - Hottenga, Jouke-Jan
AU - Arindrarto, Wibowo
AU - Claringbould, Annique
AU - van Iterson, Maarten
AU - Mei, Hailiang
AU - Franke, Lude
AU - Heijmans, Bastiaan T.
AU - 't Hoen, Peter A. C.
AU - van Meurs, Joyce
AU - Brooks, Andrew
AU - Penninx, Brenda W. J. H.
AU - Boomsma, Dorret
AU - Isaacs, Aaron
AU - Pool, Rene
AU - Hottenga, Jouke J.
AU - van Greevenbroek, Marleen M. J.
AU - Stehouwer, Coen D. A.
AU - van der Kallen, Carla J. H.
AU - Schalkwijk, Casper G.
AU - Wijmenga, Cisca
AU - Zhernakova, Sasha
AU - Tigchelaar, Ettje F.
AU - Slagboom, P. Eline
AU - Beekman, Marian
AU - Deelen, Joris
AU - van Heemst, Diana
AU - Veldink, Jan H.
AU - van den Berg, Leonard H.
AU - van Duijn, Cornelia M.
AU - Hofman, Bert A.
AU - Uitterlinden, Andre G.
AU - Jhamai, P. Mila
AU - Verbiest, Michael
AU - Suchiman, H. Eka D.
AU - Verkerk, Marijn
AU - van der Breggen, Ruud
AU - van Rooij, Jeroen
AU - Lakenberg, Nico
AU - van Galen, Michiel
AU - Bot, Jan
AU - Zhernakova, Dasha
AU - van't Hof, Peter
AU - Deelen, Patrick
AU - Nooren, Irene
AU - Moed, Matthijs
AU - BIOS Consortium
N1 - Funding Information:
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). Gen-otyping 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).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - AGE
U2 - 10.1038/s41431-019-0511-5
DO - 10.1038/s41431-019-0511-5
M3 - Article
C2 - 31558840
SN - 1018-4813
VL - 28
SP - 253
EP - 263
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 2
ER -