Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes

被引：353

作者：

Raj, Towfique ^{[1
,2
,3
,4
,5
]}

Rothamel, Katie ^{[6
]}

Mostafavi, Sara ^{[7
]}

Ye, Chun ^{[5
]}

Lee, Mark N. ^{[4
,5
]}

Replogle, Joseph M. ^{[1
,2
,5
]}

Feng, Ting ^{[6
]}

Lee, Michelle ^{[1
,2
]}

Asinovski, Natasha ^{[6
]}

Frohlich, Irene ^{[1
,2
]}

Imboywa, Selina ^{[1
,2
]}

Von Korff, Alina ^{[1
,2
]}

Okada, Yukinori ^{[3
,4
,5
,8
,9
]}

Patsopoulos, Nikolaos A. ^{[1
,2
,3
,4
,5
]}

Davis, Scott ^{[6
]}

McCabe, Cristin ^{[1
,2
,5
]}

Paik, Hyun-il ^{[6
]}

Srivastava, Gyan P. ^{[1
,2
,3
,4
,5
]}

Raychaudhuri, Soumya ^{[3
,4
,5
,10
]}

Hafler, David A. ^{[5
,11
,12
]}

Koller, Daphne ^{[7
]}

Regev, Aviv ^{[5
,13
,14
]}

Hacohen, Nir ^{[5
,15
]}

Mathis, Diane ^{[6
]}

Benoist, Christophe ^{[6
]}

Stranger, Barbara E. ^{[16
,17
]}

De Jager, Philip L. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Brigham & Womens Hosp, Programin Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Programin Translat NeuroPsychiat Genom, Inst Neurosci, Dept Psychiat, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Boston, MA 02115 USA

[5] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[6] Harvard Univ, Sch Med, Div Immunol, Microbiol & Immunobiol Immunol, Boston, MA 02115 USA

[7] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA

[8] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Divers, Tokyo, Japan

[9] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan

[10] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[11] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA

[12] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA

[13] MIT, Dept Biol, Cambridge, MA 02139 USA

[14] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[15] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02129 USA

[16] Univ Chicago, Dept Med, Sect Genet Med, Chicago, IL 60637 USA

[17] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA

来源：

SCIENCE | 2014年 / 344卷 / 6183期

关键词：

TRANSCRIPTOME;

D O I：

10.1126/science.1249547

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.

引用

页码：519 / 523

页数：5

共 16 条

[1] An integrated map of genetic variation from 1,092 human genomes
Altshuler, David M.
Durbin, Richard M.
Abecasis, Goncalo R.
Bentley, David R.
Chakravarti, Aravinda
Clark, Andrew G.
Donnelly, Peter
Eichler, Evan E.
Flicek, Paul
Gabriel, Stacey B.
Gibbs, Richard A.
Green, Eric D.
Hurles, Matthew E.
Knoppers, Bartha M.
Korbel, Jan O.
Lander, Eric S.
Lee, Charles
Lehrach, Hans
Mardis, Elaine R.
Marth, Gabor T.
McVean, Gil A.
Nickerson, Deborah A.
Schmidt, Jeanette P.
Sherry, Stephen T.
Wang, Jun
Wilson, Richard K.
Gibbs, Richard A.
Dinh, Huyen
Kovar, Christie
Lee, Sandra
Lewis, Lora
Muzny, Donna
Reid, Jeff
Wang, Min
Wang, Jun
Fang, Xiaodong
Guo, Xiaosen
Jian, Min
Jiang, Hui
Jin, Xin
Li, Guoqing
Li, Jingxiang
Li, Yingrui
Li, Zhuo
Liu, Xiao
Lu, Yao
Ma, Xuedi
Su, Zhe
Tai, Shuaishuai
Tang, Meifang
[J]. NATURE, 2012, 491 (7422) : 56 - 65
[2] Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals
Battle, Alexis
Mostafavi, Sara
Zhu, Xiaowei
Potash, James B.
Weissman, Myrna M.
McCormick, Courtney
Haudenschild, Christian D.
Beckman, Kenneth B.
Shi, Jianxin
Mei, Rui
Urban, Alexander E.
Montgomery, Stephen B.
Levinson, Douglas F.
Koller, Daphne
[J]. GENOME RESEARCH, 2014, 24 (01) : 14 - 24
[3] CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology
Bradshaw, Elizabeth M.
Chibnik, Lori B.
Keenan, Brendan T.
Ottoboni, Linda
Raj, Towfique
Tang, Anna
Rosenkrantz, Laura L.
Imboywa, Selina
Lee, Michelle
Von Korff, Alina
Morris, Martha C.
Evans, Denis A.
Johnson, Keith
Sperling, Reisa A.
Schneider, Julie A.
Bennett, David A.
De Jager, Philip L.
[J]. NATURE NEUROSCIENCE, 2013, 16 (07) : 848 - U92
[4] Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles
Fairfax, Benjamin P.
Makino, Seiko
Radhakrishnan, Jayachandran
Plant, Katharine
Leslie, Stephen
Dilthey, Alexander
Ellis, Peter
Langford, Cordelia
Vannberg, Fredrik O.
Knight, Julian C.
[J]. NATURE GENETICS, 2012, 44 (05) : 502 - +
[5] A Statistical Framework for Joint eQTL Analysis in Multiple Tissues
Flutre, Timothee
Wen, Xiaoquan
Pritchard, Jonathan
Stephens, Matthew
[J]. PLOS GENETICS, 2013, 9 (05):
[6] Mechanisms Underlying Inflammation in Neurodegeneration
Glass, Christopher K.
Saijo, Kaoru
Winner, Beate
Marchetto, Maria Carolina
Gage, Fred H.
[J]. CELL, 2010, 140 (06) : 918 - 934
[7] Random-Effects Model Aimed at Discovering Associations in Meta-Analysis of Genome-wide Association Studies
Han, Buhm
Eskin, Eleazar
[J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 88 (05) : 586 - 598
[8] Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
Hindorff, Lucia A.
Sethupathy, Praveen
Junkins, Heather A.
Ramos, Erin M.
Mehta, Jayashri P.
Collins, Francis S.
Manolio, Teri A.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (23) : 9362 - 9367
[9] Transcriptome and genome sequencing uncovers functional variation in humans
Lappalainen, Tuuli
Sammeth, Michael
Friedlaender, Marc R.
't Hoen, Peter A. C.
Monlong, Jean
Rivas, Manuel A.
Gonzalez-Porta, Mar
Kurbatova, Natalja
Griebel, Thasso
Ferreira, Pedro G.
Barann, Matthias
Wieland, Thomas
Greger, Liliana
van Iterson, Maarten
Almloef, Jonas
Ribeca, Paolo
Pulyakhina, Irina
Esser, Daniela
Giger, Thomas
Tikhonov, Andrew
Sultan, Marc
Bertier, Gabrielle
MacArthur, Daniel G.
Lek, Monkol
Lizano, Esther
Buermans, Henk P. J.
Padioleau, Ismael
Schwarzmayr, Thomas
Karlberg, Olof
Ongen, Halit
Kilpinen, Helena
Beltran, Sergi
Gut, Marta
Kahlem, Katja
Amstislavskiy, Vyacheslav
Stegle, Oliver
Pirinen, Matti
Montgomery, Stephen B.
Donnelly, Peter
McCarthy, Mark I.
Flicek, Paul
Strom, Tim M.
Lehrach, Hans
Schreiber, Stefan
Sudbrak, Ralf
Carracedo, Angel
Antonarakis, Stylianos E.
Haesler, Robert
Syvaenen, Ann-Christine
Van Ommen, Gert-Jan
[J]. NATURE, 2013, 501 (7468) : 506 - 511
[10] Systematic Localization of Common Disease-Associated Variation in Regulatory DNA
Maurano, Matthew T.
Humbert, Richard
Rynes, Eric
Thurman, Robert E.
Haugen, Eric
Wang, Hao
Reynolds, Alex P.
Sandstrom, Richard
Qu, Hongzhu
Brody, Jennifer
Shafer, Anthony
Neri, Fidencio
Lee, Kristen
Kutyavin, Tanya
Stehling-Sun, Sandra
Johnson, Audra K.
Canfield, Theresa K.
Giste, Erika
Diegel, Morgan
Bates, Daniel
Hansen, R. Scott
Neph, Shane
Sabo, Peter J.
Heimfeld, Shelly
Raubitschek, Antony
Ziegler, Steven
Cotsapas, Chris
Sotoodehnia, Nona
Glass, Ian
Sunyaev, Shamil R.
Kaul, Rajinder
Stamatoyannopoulos, John A.
[J]. SCIENCE, 2012, 337 (6099) : 1190 - 1195

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