Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis

被引：31

作者：

Polfus, Linda M. ^{[1
]}

Khajuria, Rajiv K. ^{[2
,3
,4
,5
]}

Schick, Ursula M. ^{[6
]}

Pankratz, Nathan ^{[7
]}

Pazoki, Raha ^{[8
]}

Brody, Jennifer A. ^{[9
,10
]}

Chen, Ming-Huei ^{[11
]}

Auer, Paul L. ^{[12
]}

Floyd, James S. ^{[9
,10
]}

Huang, Jie ^{[13
]}

Lange, Leslie ^{[14
]}

van Rooij, Frank J. A. ^{[8
]}

Gibbs, Richard A. ^{[15
]}

Metcalf, Ginger ^{[15
]}

Muzny, Donna ^{[15
]}

Veeraraghavan, Narayanan ^{[15
]}

Walter, Klaudia ^{[13
]}

Chen, Lu ^{[13
,16
]}

Yanek, Lisa ^{[17
]}

Becker, Lewis C. ^{[17
]}

Peloso, Gina M. ^{[18
]}

Wakabayashi, Aoi ^{[2
,3
,4
]}

Kals, Mart ^{[19
]}

Metspalu, Andres ^{[19
]}

Esko, Tonu ^{[19
]}

Fox, Keolu ^{[20
]}

Wallace, Robert ^{[21
]}

Franceschini, Nora ^{[22
]}

Matijevic, Nena ^{[23
]}

Rice, Kenneth M. ^{[9
,10
]}

Bartz, Traci M. ^{[9
,10
]}

Lyytikainen, Leo-Pekka ^{[24
,25
]}

Kahonen, Mika ^{[26
,27
]}

Lehtimaki, Terho ^{[24
,25
]}

Raitakari, Olli T. ^{[28
,29
]}

Li-Gao, Ruifang ^{[30
]}

Mook-Kanamori, Dennis O. ^{[30
,31
,32
]}

Lettre, Guillaume ^{[33
,34
]}

van Duijn, Cornelia M. ^{[35
]}

Franco, Oscar H. ^{[8
]}

Rich, Stephen S. ^{[36
]}

Rivadeneira, Fernando ^{[35
]}

Hofman, Albert ^{[35
]}

Uitterlinden, Andre G. ^{[35
]}

Wilson, James G. ^{[37
]}

Psaty, Bruce M. ^{[9
,10
,38
]}

Soranzo, Nicole ^{[13
,16
]}

Dehghan, Abbas ^{[8
]}

Boerwinkle, Eric ^{[1
]}

Zhang, Xiaoling ^{[39
,40
,41
,42
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA

[2] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

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

[5] Charite, Berlin Brandenburg Sch Regenerat Therapies, D-13353 Berlin, Germany

[6] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[7] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA

[8] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands

[9] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[10] Univ Washington, Dept Med, Seattle, WA 98195 USA

[11] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[12] Univ Wisconsin Milwaukee, Sch Publ Hlth, Milwaukee, WI 53205 USA

[13] Wellcome Trust Sanger Inst, Human Genet, Hinxton CB10 1HH, England

[14] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[15] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[16] Univ Cambridge, Dept Haematol, Cambridge CB2 0AH, England

[17] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program,Div Gen Internal Med, Baltimore, MD 21205 USA

[18] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[19] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia

[20] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[21] Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA

[22] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA

[23] Univ Texas Hlth Sci Ctr Houston, Dept Surg, Houston, TX 77030 USA

[24] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland

[25] Univ Tampere, Sch Med, Tampere 33520, Finland

[26] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland

[27] Univ Tampere, Sch Med, Tampere 33521, Finland

[28] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20520, Finland

[29] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland

[30] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RA Leiden, Netherlands

[31] King Faisal Specialist Hosp & Res Ctr, Dept Biostat, Epidemiol, Epidemiol Sect, Riyadh 11211, Saudi Arabia

[32] King Faisal Specialist Hosp & Res Ctr, Dept Comp Sci, Riyadh 11211, Saudi Arabia

[33] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[34] Univ Montreal, Montreal, PQ H1T 1C8, Canada

[35] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands

[36] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA

[37] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA

[38] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA

[39] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[40] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA

[41] Boston Univ, Sch Publ Hlth, Dept Med, Boston, MA 02118 USA

[42] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[43] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA 01702 USA

[44] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA

[45] Bloodworks Northwest, Seattle, WA 98102 USA

[46] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Womens Hlth Initiat Clin Coordinating Ctr, Seattle, WA 98109 USA

[47] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA

[48] Univ Michigan, Dept Human Genet, Div Cardiovasc Med, Ann Arbor, MI 48109 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2016年 / 99卷 / 02期

基金：

英国惠康基金;

关键词：

DIAMOND-BLACKFAN ANEMIA; GRAY PLATELET SYNDROME; HEMATOLOGICAL TRAITS; GENETIC-VARIATION; GFI-1B; DIFFERENTIATION; METAANALYSIS; CONSORTIUM; MUTATIONS; DISORDER;

D O I：

10.1016/j.ajhg.2016.06.016

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF=0.33, discovery + replication p=6.38 x 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF=0.009, discovery + replication p=1.79 x 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis.

引用

页码：481 / 488

页数：8

共 33 条

[1] Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome [J].

Albers, Cornelis A. ;

Cvejic, Ana ;

Favier, Remi ;

Bouwmans, Evelien E. ;

Alessi, Marie-Christine ;

Bertone, Paul ;

Jordan, Gregory ;

Kettleborough, Ross N. W. ;

Kiddle, Graham ;

Kostadima, Myrto ;

Read, Randy J. ;

Sipos, Botond ;

Sivapalaratnam, Suthesh ;

Smethurst, Peter A. ;

Stephens, Jonathan ;

Voss, Katrin ;

Nurden, Alan ;

Rendon, Augusto ;

Nurden, Paquita ;

Ouwehand, Willem H. .

NATURE GENETICS, 2011, 43 (08) :735-737

[2] Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits [J].

Auer, Paul L. ;

Teumer, Alexander ;

Schick, Ursula ;

O'Shaughnessy, Andrew ;

Lo, Ken Sin ;

Chami, Nathalie ;

Carlson, Chris ;

de Denus, Simon ;

Dube, Marie-Pierre ;

Haessler, Jeff ;

Jackson, Rebecca D. ;

Kooperberg, Charles ;

Perreault, Louis-Philippe Lemieux ;

Nauck, Matthias ;

Peters, Ulrike ;

Rioux, John D. ;

Schmidt, Frank ;

Turcot, Valerie ;

Voelker, Uwe ;

Voelzke, Henry ;

Greinacher, Andreas ;

Hsu, Li ;

Tardif, Jean-Claude ;

Diaz, George A. ;

Reiner, Alexander P. ;

Lettre, Guillaume .

NATURE GENETICS, 2014, 46 (06) :629-634

[3] Atherosclerosis Risk in Communities (ARIC) carotid MRI flow cytometry study of monocyte and platelet markers: Intraindividual variability and reliability [J].

Catellier, Diane J. ;

Aleksic, Nena ;

Folsom, Aaron R. ;

Boerwinkle, Eric .

CLINICAL CHEMISTRY, 2008, 54 (08) :1363-1371

[4] Transcriptional diversity during lineage commitment of human blood progenitors [J].

Chen, Lu ;

Kostadima, Myrto ;

Martens, Joost H. A. ;

Canu, Giovanni ;

Garcia, Sara P. ;

Turro, Ernest ;

Downes, Kate ;

Macaulay, Iain C. ;

Bielczyk-Maczynska, Ewa ;

Coe, Sophia ;

Farrow, Samantha ;

Poudel, Pawan ;

Burden, Frances ;

Jansen, Sjoert B. G. ;

Astle, William J. ;

Attwood, Antony ;

Bariana, Tadbir ;

de Bono, Bernard ;

Breschi, Alessandra ;

Chambers, John C. ;

Choudry, Fizzah A. ;

Clarke, Laura ;

Coupland, Paul ;

van der Ent, Martijn ;

Erber, Wendy N. ;

Jansen, Joop H. ;

Favier, Remi ;

Fenech, Matthew E. ;

Foad, Nicola ;

Freson, Kathleen ;

van Geet, Chris ;

Gomez, Keith ;

Guigo, Roderic ;

Hampshire, Daniel ;

Kelly, Anne M. ;

Kerstens, Hindrik H. D. ;

Kooner, Jaspal S. ;

Laffan, Michael ;

Lentaigne, Claire ;

Labalette, Charlotte ;

Martin, Tiphaine ;

Meacham, Stuart ;

Mumford, Andrew ;

Nuernberg, Sylvia ;

Palumbo, Emilio ;

van der Reijden, Bert A. ;

Richardson, David ;

Sammut, Stephen J. ;

Slodkowicz, Greg ;

Tamuri, Asif U. .

SCIENCE, 2014, 345 (6204) :1580-+

[5] Interaction between the RNA binding domains of Ser-Arg splicing factor 1 and U1-70K snRNP protein determines early spliceosome assembly [J].

Cho, Suhyung ;

Hoang, Amy ;

Sinha, Rahul ;

Zhong, Xiang-Yang ;

Fu, Xiang-Dong ;

Krainer, Adrian R. ;

Ghosh, Gourisankar .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (20) :8233-8238

[6] Distinct, strict requirements for Gfi-1b in adult bone marrow red cell and platelet generation [J].

Foudi, Adlen ;

Kramer, Daniel J. ;

Qin, Jinzhong ;

Ye, Denise ;

Behlich, Anna-Sophie ;

Mordecai, Scott ;

Preffer, Frederic I. ;

Amzallag, Arnaud ;

Ramaswamy, Sridhar ;

Hochedlinger, Konrad ;

Orkin, Stuart H. ;

Hock, Hanno .

JOURNAL OF EXPERIMENTAL MEDICINE, 2014, 211 (05) :909-927

[7] Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium [J].

Ganesh, Santhi K. ;

Zakai, Neil A. ;

van Rooij, Frank J. A. ;

Soranzo, Nicole ;

Smith, Albert V. ;

Nalls, Michael A. ;

Chen, Ming-Huei ;

Kottgen, Anna ;

Glazer, Nicole L. ;

Dehghan, Abbas ;

Kuhnel, Brigitte ;

Aspelund, Thor ;

Yang, Qiong ;

Tanaka, Toshiko ;

Jaffe, Andrew ;

Bis, Joshua C. M. ;

Verwoert, Germaine C. ;

Teumer, Alexander ;

Fox, Caroline S. ;

Guralnik, Jack M. ;

Ehret, Georg B. ;

Rice, Kenneth ;

Felix, Janine F. ;

Rendon, Augusto ;

Eiriksdottir, Gudny ;

Levy, Daniel ;

Patel, Kushang V. ;

Boerwinkle, Eric ;

Rotter, Jerome I. ;

Hofman, Albert ;

Sambrook, Jennifer G. ;

Hernandez, Dena G. ;

Zheng, Gang ;

Bandinelli, Stefania ;

Singleton, Andrew B. ;

Coresh, Josef ;

Lumley, Thomas ;

Uitterlinden, Andre G. ;

vanGils, Janine M. ;

Launer, Lenore J. ;

Cupples, L. Adrienne ;

Oostra, Ben A. ;

Zwaginga, Jaap-Jan ;

Ouwehand, Willem H. ;

Thein, Swee-Lay ;

Meisinger, Christa ;

Deloukas, Panos ;

Nauck, Matthias ;

Spector, Tim D. ;

Gieger, Christian .

NATURE GENETICS, 2009, 41 (11) :1191-U48

[8] Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells [J].

Giani, Felix C. ;

Fiorini, Claudia ;

Wakabayashi, Aoi ;

Ludwig, Leif S. ;

Salem, Rany M. ;

Jobaliya, Chintan D. ;

Regan, Stephanie N. ;

Ulirsch, Jacob C. ;

Liang, Ge ;

Steinberg-Shemer, Orna ;

Guo, Michael H. ;

Esko, Tonu ;

Tong, Wei ;

Brugnara, Carlo ;

Hirschhorn, Joel N. ;

Weiss, Mitchell J. ;

Zon, Leonard I. ;

Chou, Stella T. ;

French, Deborah L. ;

Musunuru, Kiran ;

Sankaran, Vijay G. .

CELL STEM CELL, 2016, 18 (01) :73-78

[9] Massively parallel sequencing: the new frontier of hematologic genomics [J].

Johnsen, Jill M. ;

Nickerson, Deborah A. ;

Reiner, Alex P. .

BLOOD, 2013, 122 (19) :3268-3275

[10] New loci associated with kidney function and chronic kidney disease [J].

Koettgen, Anna ;

Pattaro, Cristian ;

Boeger, Carsten A. ;

Fuchsberger, Christian ;

Olden, Matthias ;

Glazer, Nicole L. ;

Parsa, Afshin ;

Gao, Xiaoyi ;

Yang, Qiong ;

Smith, Albert V. ;

O'Connell, Jeffrey R. ;

Li, Man ;

Schmidt, Helena ;

Tanaka, Toshiko ;

Isaacs, Aaron ;

Ketkar, Shamika ;

Hwang, Shih-Jen ;

Johnson, Andrew D. ;

Dehghan, Abbas ;

Teumer, Alexander ;

Pare, Guillaume ;

Atkinson, Elizabeth J. ;

Zeller, Tanja ;

Lohman, Kurt ;

Cornelis, Marilyn C. ;

Probst-Hensch, Nicole M. ;

Kronenberg, Florian ;

Toenjes, Anke ;

Hayward, Caroline ;

Aspelund, Thor ;

Eiriksdottir, Gudny ;

Launer, Lenore J. ;

Harris, Tamara B. ;

Rampersaud, Evadnie ;

Mitchell, Braxton D. ;

Arking, Dan E. ;

Boerwinkle, Eric ;

Struchalin, Maksim ;

Cavalieri, Margherita ;

Singleton, Andrew ;

Giallauria, Francesco ;

Metter, Jeffrey ;

de Boer, Ian H. ;

Haritunians, Talin ;

Lumley, Thomas ;

Siscovick, David ;

Psaty, Bruce M. ;

Zillikens, M. Carola ;

Oostra, Ben A. ;

Feitosa, Mary .

NATURE GENETICS, 2010, 42 (05) :376-U34

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