Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

Lu Chen; Bing Ge; Francesco Paolo Casale; Louella Vasquez; Tony Kwan; Diego Garrido-Martín; Stephen Watt; Ying Yan; Kousik Kundu; Simone Ecker; Avik Datta; David Richardson; Frances Burden; Daniel Mead; Alice L. Mann; Jose Maria Fernandez; Sophia Rowlston; Steven P. Wilder; Samantha Farrow; Xiaojian Shao; John J. Lambourne; Adriana Redensek; Cornelis A. Albers; Vyacheslav Amstislavskiy; Sofie Ashford; Kim Berentsen; Lorenzo Bomba; Guillaume Bourque; David Bujold; Stephan Busche; Maxime Caron; Shu-Huang Chen; Warren Cheung; Oliver Delaneau; Emmanouil T. Dermitzakis; Heather Elding; Irina Colgiu; Frederik O. Bagger; Paul Flicek; Ehsan Habibi; Valentina Iotchkova; Eva Janssen-Megens; Bowon Kim; Hans Lehrach; Ernesto Lowy; Amit Mandoli; Filomena Matarese; Matthew T. Maurano; John A. Morris; Vera Pancaldi; Farzin Pourfarzad; Karola Rehnstrom; Augusto Rendon; Thomas Risch; Nilofar Sharifi; Marie-Michelle Simon; Marc Sultan; Alfonso Valencia; Klaudia Walter; Shuang-Yin Wang; Mattia Frontini; Stylianos E. Antonarakis; Laura Clarke; Marie-Laure Yaspo; Stephan Beck; Roderic Guigo; Daniel Rico; Joost H. A. Martens; Willem H. Ouwehand; Taco W. Kuijpers; Dirk S. Paul; Hendrik G. Stunnenberg; Oliver Stegle; Kate Downes; Tomi Pastinen; Nicole Soranzo

doi:https://doi.org/10.1016/j.cell.2016.10.026

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

Lu Chen, Bing Ge, Francesco Paolo Casale, Louella Vasquez, Tony Kwan, Diego Garrido-Martín, Stephen Watt, Ying Yan, Kousik Kundu, Simone Ecker, Avik Datta, David Richardson, Frances Burden, Daniel Mead, Alice L. Mann, Jose Maria Fernandez, Sophia Rowlston, Steven P. Wilder, Samantha Farrow, Xiaojian ShaoJohn J. Lambourne, Adriana Redensek, Cornelis A. Albers, Vyacheslav Amstislavskiy, Sofie Ashford, Kim Berentsen, Lorenzo Bomba, Guillaume Bourque, David Bujold, Stephan Busche, Maxime Caron, Shu-Huang Chen, Warren Cheung, Oliver Delaneau, Emmanouil T. Dermitzakis, Heather Elding, Irina Colgiu, Frederik O. Bagger, Paul Flicek, Ehsan Habibi, Valentina Iotchkova, Eva Janssen-Megens, Bowon Kim, Hans Lehrach, Ernesto Lowy, Amit Mandoli, Filomena Matarese, Matthew T. Maurano, John A. Morris, Vera Pancaldi, Farzin Pourfarzad, Karola Rehnstrom, Augusto Rendon, Thomas Risch, Nilofar Sharifi, Marie-Michelle Simon, Marc Sultan, Alfonso Valencia, Klaudia Walter, Shuang-Yin Wang, Mattia Frontini, Stylianos E. Antonarakis, Laura Clarke, Marie-Laure Yaspo, Stephan Beck, Roderic Guigo, Daniel Rico, Joost H. A. Martens, Willem H. Ouwehand, Taco W. Kuijpers, Dirk S. Paul, Hendrik G. Stunnenberg, Oliver Stegle, Kate Downes, Tomi Pastinen, Nicole Soranzo

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Abstract

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14(+) monocytes, CD16(+) neutrophils, and naive CD4(+) T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk

Original language	English
Pages (from-to)	1398-1414.e24
Journal	Cell
Volume	167
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2016.10.026
Publication status	Published - 2016

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https://doi.org/10.1016/j.cell.2016.10.026

Cite this

Chen, L., Ge, B., Casale, F. P., Vasquez, L., Kwan, T., Garrido-Martín, D., Watt, S., Yan, Y., Kundu, K., Ecker, S., Datta, A., Richardson, D., Burden, F., Mead, D., Mann, A. L., Fernandez, J. M., Rowlston, S., Wilder, S. P., Farrow, S., ... Soranzo, N. (2016). Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells. Cell, 167(5), 1398-1414.e24. https://doi.org/10.1016/j.cell.2016.10.026

@article{619d1383d5b44f58ad1226d4e7798909,

title = "Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells",

abstract = "Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14(+) monocytes, CD16(+) neutrophils, and naive CD4(+) T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk",

author = "Lu Chen and Bing Ge and Casale, {Francesco Paolo} and Louella Vasquez and Tony Kwan and Diego Garrido-Mart{\'i}n and Stephen Watt and Ying Yan and Kousik Kundu and Simone Ecker and Avik Datta and David Richardson and Frances Burden and Daniel Mead and Mann, {Alice L.} and Fernandez, {Jose Maria} and Sophia Rowlston and Wilder, {Steven P.} and Samantha Farrow and Xiaojian Shao and Lambourne, {John J.} and Adriana Redensek and Albers, {Cornelis A.} and Vyacheslav Amstislavskiy and Sofie Ashford and Kim Berentsen and Lorenzo Bomba and Guillaume Bourque and David Bujold and Stephan Busche and Maxime Caron and Shu-Huang Chen and Warren Cheung and Oliver Delaneau and Dermitzakis, {Emmanouil T.} and Heather Elding and Irina Colgiu and Bagger, {Frederik O.} and Paul Flicek and Ehsan Habibi and Valentina Iotchkova and Eva Janssen-Megens and Bowon Kim and Hans Lehrach and Ernesto Lowy and Amit Mandoli and Filomena Matarese and Maurano, {Matthew T.} and Morris, {John A.} and Vera Pancaldi and Farzin Pourfarzad and Karola Rehnstrom and Augusto Rendon and Thomas Risch and Nilofar Sharifi and Marie-Michelle Simon and Marc Sultan and Alfonso Valencia and Klaudia Walter and Shuang-Yin Wang and Mattia Frontini and Antonarakis, {Stylianos E.} and Laura Clarke and Marie-Laure Yaspo and Stephan Beck and Roderic Guigo and Daniel Rico and Martens, {Joost H. A.} and Ouwehand, {Willem H.} and Kuijpers, {Taco W.} and Paul, {Dirk S.} and Stunnenberg, {Hendrik G.} and Oliver Stegle and Kate Downes and Tomi Pastinen and Nicole Soranzo",

year = "2016",

doi = "https://doi.org/10.1016/j.cell.2016.10.026",

language = "English",

volume = "167",

pages = "1398--1414.e24",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "5",

}

Chen, L, Ge, B, Casale, FP, Vasquez, L, Kwan, T, Garrido-Martín, D, Watt, S, Yan, Y, Kundu, K, Ecker, S, Datta, A, Richardson, D, Burden, F, Mead, D, Mann, AL, Fernandez, JM, Rowlston, S, Wilder, SP, Farrow, S, Shao, X, Lambourne, JJ, Redensek, A, Albers, CA, Amstislavskiy, V, Ashford, S, Berentsen, K, Bomba, L, Bourque, G, Bujold, D, Busche, S, Caron, M, Chen, S-H, Cheung, W, Delaneau, O, Dermitzakis, ET, Elding, H, Colgiu, I, Bagger, FO, Flicek, P, Habibi, E, Iotchkova, V, Janssen-Megens, E, Kim, B, Lehrach, H, Lowy, E, Mandoli, A, Matarese, F, Maurano, MT, Morris, JA, Pancaldi, V, Pourfarzad, F, Rehnstrom, K, Rendon, A, Risch, T, Sharifi, N, Simon, M-M, Sultan, M, Valencia, A, Walter, K, Wang, S-Y, Frontini, M, Antonarakis, SE, Clarke, L, Yaspo, M-L, Beck, S, Guigo, R, Rico, D, Martens, JHA, Ouwehand, WH, Kuijpers, TW, Paul, DS, Stunnenberg, HG, Stegle, O, Downes, K, Pastinen, T & Soranzo, N 2016, 'Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells', Cell, vol. 167, no. 5, pp. 1398-1414.e24. https://doi.org/10.1016/j.cell.2016.10.026

TY - JOUR

T1 - Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

AU - Chen, Lu

AU - Ge, Bing

AU - Casale, Francesco Paolo

AU - Vasquez, Louella

AU - Kwan, Tony

AU - Garrido-Martín, Diego

AU - Watt, Stephen

AU - Yan, Ying

AU - Kundu, Kousik

AU - Ecker, Simone

AU - Datta, Avik

AU - Richardson, David

AU - Burden, Frances

AU - Mead, Daniel

AU - Mann, Alice L.

AU - Fernandez, Jose Maria

AU - Rowlston, Sophia

AU - Wilder, Steven P.

AU - Farrow, Samantha

AU - Shao, Xiaojian

AU - Lambourne, John J.

AU - Redensek, Adriana

AU - Albers, Cornelis A.

AU - Amstislavskiy, Vyacheslav

AU - Ashford, Sofie

AU - Berentsen, Kim

AU - Bomba, Lorenzo

AU - Bourque, Guillaume

AU - Bujold, David

AU - Busche, Stephan

AU - Caron, Maxime

AU - Chen, Shu-Huang

AU - Cheung, Warren

AU - Delaneau, Oliver

AU - Dermitzakis, Emmanouil T.

AU - Elding, Heather

AU - Colgiu, Irina

AU - Bagger, Frederik O.

AU - Flicek, Paul

AU - Habibi, Ehsan

AU - Iotchkova, Valentina

AU - Janssen-Megens, Eva

AU - Kim, Bowon

AU - Lehrach, Hans

AU - Lowy, Ernesto

AU - Mandoli, Amit

AU - Matarese, Filomena

AU - Maurano, Matthew T.

AU - Morris, John A.

AU - Pancaldi, Vera

AU - Pourfarzad, Farzin

AU - Rehnstrom, Karola

AU - Rendon, Augusto

AU - Risch, Thomas

AU - Sharifi, Nilofar

AU - Simon, Marie-Michelle

AU - Sultan, Marc

AU - Valencia, Alfonso

AU - Walter, Klaudia

AU - Wang, Shuang-Yin

AU - Frontini, Mattia

AU - Antonarakis, Stylianos E.

AU - Clarke, Laura

AU - Yaspo, Marie-Laure

AU - Beck, Stephan

AU - Guigo, Roderic

AU - Rico, Daniel

AU - Martens, Joost H. A.

AU - Ouwehand, Willem H.

AU - Kuijpers, Taco W.

AU - Paul, Dirk S.

AU - Stunnenberg, Hendrik G.

AU - Stegle, Oliver

AU - Downes, Kate

AU - Pastinen, Tomi

AU - Soranzo, Nicole

PY - 2016

Y1 - 2016

N2 - Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14(+) monocytes, CD16(+) neutrophils, and naive CD4(+) T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk

AB - Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14(+) monocytes, CD16(+) neutrophils, and naive CD4(+) T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk

U2 - https://doi.org/10.1016/j.cell.2016.10.026

DO - https://doi.org/10.1016/j.cell.2016.10.026

M3 - Article

C2 - 27863251

SN - 0092-8674

VL - 167

SP - 1398-1414.e24

JO - Cell

JF - Cell

IS - 5

ER -