Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

被引：470

作者：

Chen, Lu ^{[1
,2
]}

Ge, Bing ^{[3
]}

Casale, Francesco Paolo ^{[4
]}

Vasquez, Louella ^{[1
]}

Kwan, Tony ^{[3
]}

Garrido-Martin, Diego ^{[5
,6
]}

Watt, Stephen ^{[1
]}

Yan, Ying ^{[1
]}

Kundu, Kousik ^{[1
,2
]}

Ecker, Simone ^{[7
,8
]}

Datta, Avik ^{[9
]}

Richardson, David ^{[9
]}

Burden, Frances ^{[2
,18
]}

Mead, Daniel ^{[1
]}

Mann, Alice L. ^{[1
]}

Maria Fernandez, Jose ^{[7
]}

Rowlston, Sophia ^{[2
,18
]}

Wilder, Steven P. ^{[10
]}

Farrow, Samantha ^{[2
,18
]}

Shao, Xiaojian ^{[3
]}

Lambourne, John J. ^{[2
,3
,18
]}

Redensek, Adriana ^{[3
]}

Albers, Cornelis A. ^{[13
,16
]}

Amstislavskiy, Vyacheslav ^{[14
]}

Ashford, Sofie ^{[2
,18
]}

Berentsen, Kim ^{[15
]}

Bomba, Lorenzo ^{[1
]}

Bourque, Guillaume ^{[3
]}

Bujold, David ^{[3
]}

Busche, Stephan ^{[3
]}

Caron, Maxime ^{[3
]}

Chen, Shu-Huang ^{[3
]}

Cheung, Warren ^{[3
]}

Delaneau, Oliver ^{[12
]}

Dermitzakis, Emmanouil T. ^{[12
]}

Elding, Heather ^{[1
]}

Colgiu, Irina ^{[17
]}

Bagger, Frederik O. ^{[2
,4
,18
]}

Flicek, Paul ^{[9
]}

Habibi, Ehsan ^{[15
]}

Iotchkova, Valentina ^{[1
,11
]}

Janssen-Megens, Eva ^{[15
]}

Kim, Bowon ^{[15
]}

Lehrach, Hans ^{[14
]}

Lowy, Ernesto ^{[9
]}

Mandoli, Amit ^{[15
]}

Matarese, Filomena ^{[15
]}

Maurano, Matthew T. ^{[19
]}

Morris, John A. ^{[3
]}

Pancaldi, Vera ^{[7
]}

机构：

[1] Wellcome Trust Sanger Inst, Dept Human Genet, Wellcome Trust Genome Campus, Cambridge CB10 1HH, England

[2] Univ Cambridge, Dept Haematol, Cambridge Biomed Campus,Long Rd, Cambridge CB2 0PT, England

[3] McGill Univ, Human Genet, 740 Dr Penfield, Montreal, PQ H3A 0G1, Canada

[4] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England

[5] Barcelona Inst Sci & Technol, CRG, Bioinformat & Genom, Carrer Dr Aiguader 88, Barcelona 8003, Spain

[6] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Placa de la Merce 10-12, Barcelona 8002, Spain

[7] Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Programme, Melchor Fernandez Almagro 3, Madrid 28029, Spain

[8] UCL, Inst Canc, 72 Huntley St, London WC1E 6BT, England

[9] European Bioinformat Inst, European Mol Biol Lab, Vertebrate Genom, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[10] European Bioinformat Inst, European Mol Biol Lab, Genome Anal, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[11] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[12] Univ Geneva, Med Sch CMU, Genet Med & Dev, 1 Rue Michel Servet, CH-1211 Geneva, Switzerland

[13] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Human Genet, POB 9101, NL-6500 HB Nijmegen, Netherlands

[14] Max Planck Inst Mol Genet, Dept Vertebrate Genom, Ihnestr 63-73, D-14195 Berlin, Germany

[15] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6525 GA Nijmegen, Netherlands

[16] Radboud Univ Nijmegen, Radboud Inst Life Sci, Mol Dev Biol, POB 9101, NL-6500 HB Nijmegen, Netherlands

[17] Wellcome Trust Sanger Inst, Human Genet Informat, Wellcome Trust Genome Campus, Cambridge CB10 1HH, England

[18] Natl Hlth Serv NHS Blood & Transplant, Cambridge Biomed Campus,Long Rd, Cambridge CB2 0PT, England

[19] NYU, Inst Syst Genet, Langone Med Ctr, ACLS West, Room 511,430 East 29th St, New York, NY 10016 USA

[20] Sanquin Res & Landsteiner Lab, Blood Cell Res, Plesmanlaan 125, NL-1066 CX Amsterdam, Netherlands

[21] Genom England, Bioinformat, Charterhouse Sq, London EC1M 6BQ, England

[22] Addenbrookes Hosp, British Heart Fdn Ctr Excellence, Div Cardiovasc Med, Hills Rd, Cambridge CB2 0QQ, England

[23] Inst Hosp Mar Invest Med IMIM, Computat Genom, Carrer Dr Aiguader 88, Barcelona 8003, Spain

[24] Newcastle Univ, Inst Cellular Med, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[25] Univ Cambridge, Strangeways Res Lab, Natl Inst Hlth Res Blood & Transplant Unit NIHR B, Worts Causeway, Cambridge CB1 8RN, England

[26] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Locat H7-230,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[27] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cardiovasc Epidemiol Unit, Worts Causeway, Cambridge CB1 8RN, England

来源：

CELL | 2016年 / 167卷 / 05期

基金：

英国惠康基金; 英国医学研究理事会; 加拿大健康研究院;

关键词：

WHOLE-GENOME ASSOCIATION; TEC FAMILY KINASES; DNA METHYLATION; SUSCEPTIBILITY LOCI; EXPRESSION; DISEASE; ARCHITECTURE; DISCOVERY; VARIANTS; SEQ;

D O I：

10.1016/j.cell.2016.10.026

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1398 / +

页数：41

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