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 I. Brooks, Dorret I. Boomsma, Brenda W. J. H. Penninx, BIOS Consortium

Research output: Contribution to journalArticleAcademicpeer-review

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 h2 total, composed of cis-heritability (h2 cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2 res, the residual variance explained by all other genome-wide variants). Mean h2 total 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 h2 cis 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 h2 res 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.
Original languageEnglish
Pages (from-to)253-263
JournalEuropean Journal of Human Genetics
Volume28
Issue number2
Early online date2019
DOIs
Publication statusPublished - Feb 2020

Cite this

Ouwens, K. G., Jansen, R., Nivard, M. G., van Dongen, J., Frieser, M. J., Hottenga, J-J., ... BIOS Consortium (2020). A characterization of cis- and trans-heritability of RNA-Seq-based gene expression. European Journal of Human Genetics, 28(2), 253-263. https://doi.org/10.1038/s41431-019-0511-5
Ouwens, Klaasjan G. ; Jansen, Rick ; Nivard, Michel G. ; van Dongen, Jenny ; Frieser, Maia J. ; Hottenga, Jouke-Jan ; Arindrarto, Wibowo ; Claringbould, Annique ; van Iterson, Maarten ; Mei, Hailiang ; Franke, Lude ; Heijmans, Bastiaan T. ; A. C. ’t Hoen, Peter ; van Meurs, Joyce ; Brooks, Andrew I. ; Boomsma, Dorret I. ; Penninx, Brenda W. J. H. ; BIOS Consortium. / A characterization of cis- and trans-heritability of RNA-Seq-based gene expression. In: European Journal of Human Genetics. 2020 ; Vol. 28, No. 2. pp. 253-263.
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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 h2 total, composed of cis-heritability (h2 cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2 res, the residual variance explained by all other genome-wide variants). Mean h2 total 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 h2 cis 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 h2 res 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.",
author = "Ouwens, {Klaasjan G.} and Rick Jansen and Nivard, {Michel G.} and {van Dongen}, Jenny and Frieser, {Maia J.} and Jouke-Jan Hottenga and Wibowo Arindrarto and Annique Claringbould and {van Iterson}, Maarten and Hailiang Mei and Lude Franke and Heijmans, {Bastiaan T.} and {A. C. ’t Hoen}, Peter and {van Meurs}, Joyce and Brooks, {Andrew I.} and Aaron Isaacs and Rick Jansen and Lude Franke and Boomsma, {Dorret I.} and Ren{\'e} Pool and {van Dongen}, Jenny and Hottenga, {Jouke J.} and {van Greevenbroek}, {Marleen M. J.} and Stehouwer, {Coen D. A.} and {van der Kallen}, {Carla J. H.} and Schalkwijk, {Casper G.} and Cisca Wijmenga and Lude Franke and Sasha Zhernakova and Tigchelaar, {Ettje F.} and Slagboom, {P. Eline} and Marian Beekman and Joris Deelen and {van Heemst}, Diana and Veldink, {Jan H.} and {van den Berg}, {Leonard H.} and Rick Jansen and {van Dijk}, Freerk and Rick Jansen and Penninx, {Brenda W. J. H.} and {BIOS Consortium} and {van Dongen}, Jenny and Schalkwijk, {Casper G.} and {van den Berg}, {Leonard H.} and {van Dijk}, Freerk and Rick Jansen",
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Ouwens, KG, Jansen, R, Nivard, MG, van Dongen, J, Frieser, MJ, Hottenga, J-J, Arindrarto, W, Claringbould, A, van Iterson, M, Mei, H, Franke, L, Heijmans, BT, A. C. ’t Hoen, P, van Meurs, J, Brooks, AI, Boomsma, DI, Penninx, BWJH & BIOS Consortium 2020, 'A characterization of cis- and trans-heritability of RNA-Seq-based gene expression' European Journal of Human Genetics, vol. 28, no. 2, pp. 253-263. https://doi.org/10.1038/s41431-019-0511-5

A characterization of cis- and trans-heritability of RNA-Seq-based gene expression. / Ouwens, Klaasjan G.; Jansen, Rick; Nivard, Michel G.; van Dongen, Jenny; Frieser, Maia J.; Hottenga, Jouke-Jan; Arindrarto, Wibowo; Claringbould, Annique; van Iterson, Maarten; Mei, Hailiang; Franke, Lude; Heijmans, Bastiaan T.; A. C. ’t Hoen, Peter; van Meurs, Joyce; Brooks, Andrew I.; Boomsma, Dorret I.; Penninx, Brenda W. J. H.; BIOS Consortium.

In: European Journal of Human Genetics, Vol. 28, No. 2, 02.2020, p. 253-263.

Research output: Contribution to journalArticleAcademicpeer-review

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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 - A. C. ’t Hoen, Peter

AU - van Meurs, Joyce

AU - Brooks, Andrew I.

AU - Isaacs, Aaron

AU - Jansen, Rick

AU - Franke, Lude

AU - Boomsma, Dorret I.

AU - Pool, René

AU - van Dongen, Jenny

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 - Franke, Lude

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 - Jansen, Rick

AU - van Dijk, Freerk

AU - Jansen, Rick

AU - Penninx, Brenda W. J. H.

AU - BIOS Consortium

AU - van Dongen, Jenny

AU - Schalkwijk, Casper G.

AU - van den Berg, Leonard H.

AU - van Dijk, Freerk

AU - Jansen, Rick

PY - 2020/2

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AB - 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 h2 total, composed of cis-heritability (h2 cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2 res, the residual variance explained by all other genome-wide variants). Mean h2 total 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 h2 cis 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 h2 res 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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