A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects

被引：103

作者：

Shameer, Khader ^{[1
]}

Denny, Joshua C. ^{[2
,3
]}

Ding, Keyue ^{[1
]}

Jouni, Hayan ^{[1
]}

Crosslin, David R. ^{[4
]}

de Andrade, Mariza ^{[5
]}

Chute, Christopher G. ^{[5
]}

Peissig, Peggy ^{[6
]}

Pacheco, Jennifer A. ^{[7
]}

Li, Rongling ^{[8
]}

Bastarache, Lisa ^{[2
,3
]}

Kho, Abel N. ^{[9
]}

Ritchie, Marylyn D. ^{[10
]}

Masys, Daniel R. ^{[11
]}

Chisholm, Rex L. ^{[7
]}

Larson, Eric B. ^{[12
]}

McCarty, Catherine A. ^{[13
]}

Roden, Dan M. ^{[14
]}

Jarvik, Gail P. ^{[15
]}

Kullo, Iftikhar J. ^{[1
]}

机构：

[1] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA

[2] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA

[4] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[5] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA

[6] Marshfield Clin Fdn Med Res & Educ, Biomed Informat Res Ctr, Marshfield, WI 54449 USA

[7] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

[8] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA

[9] Northwestern Univ, Dept Med, Chicago, IL 60611 USA

[10] Penn State Univ, Eberly Coll Sci, Huck Inst Life Sci, Ctr Syst Genom, University Pk, PA 16802 USA

[11] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37232 USA

[12] Grp Hlth Res Inst, Seattle, WA 98101 USA

[13] Essentia Inst Rural Hlth, Duluth, MN 55805 USA

[14] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA

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

来源：

HUMAN GENETICS | 2014年 / 133卷 / 01期

关键词：

ELECTRONIC MEDICAL-RECORDS; ANKYLOSING-SPONDYLITIS; BLOOD-PRESSURE; DISEASE; PATHWAYS; PHEWAS; REGION; PROTEOLYSIS; METASTASIS; SEQUENCE;

D O I：

10.1007/s00439-013-1355-7

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (alpha: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (alpha: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.

引用

页码：95 / 109

页数：15

共 84 条

[71] A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium [J].

Soranzo, Nicole ;

Spector, Tim D. ;

Mangino, Massimo ;

Kuehnel, Brigitte ;

Rendon, Augusto ;

Teumer, Alexander ;

Willenborg, Christina ;

Wright, Benjamin ;

Chen, Li ;

Li, Mingyao ;

Salo, Perttu ;

Voight, Benjamin F. ;

Burns, Philippa ;

Laskowski, Roman A. ;

Xue, Yali ;

Menzel, Stephan ;

Altshuler, David ;

Bradley, John R. ;

Bumpstead, Suzannah ;

Burnett, Mary-Susan ;

Devaney, Joseph ;

Doering, Angela ;

Elosua, Roberto ;

Epstein, Stephen E. ;

Erber, Wendy ;

Falchi, Mario ;

Garner, Stephen F. ;

Ghori, Mohammed J. R. ;

Goodall, Alison H. ;

Gwilliam, Rhian ;

Hakonarson, Hakon H. ;

Hall, Alistair S. ;

Hammond, Naomi ;

Hengstenberg, Christian ;

Illig, Thomas ;

Koenig, Inke R. ;

Knouff, Christopher W. ;

McPherson, Ruth ;

Melander, Olle ;

Mooser, Vincent ;

Nauck, Matthias ;

Nieminen, Markku S. ;

O'Donnell, Christopher J. ;

Peltonen, Leena ;

Potter, Simon C. ;

Prokisch, Holger ;

Rader, Daniel J. ;

Rice, Catherine M. ;

Roberts, Robert ;

Salomaa, Veikko .

NATURE GENETICS, 2009, 41 (11) :1182-U38

[72] A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function [J].

Soranzo, Nicole ;

Rendon, Augusto ;

Gieger, Christian ;

Jones, Chris I. ;

Watkins, Nicholas A. ;

Menzel, Stephan ;

Doering, Angela ;

Stephens, Jonathan ;

Prokisch, Holger ;

Erber, Wendy ;

Potter, Simon C. ;

Bray, Sarah L. ;

Burns, Philippa ;

Jolley, Jennifer ;

Falchi, Mario ;

Kuehnel, Brigitte ;

Erdmann, Jeanette ;

Schunkert, Heribert ;

Samani, Nilesh J. ;

Illig, Thomas ;

Garner, Stephen F. ;

Rankin, Angela ;

Meisinger, Christa ;

Bradley, John R. ;

Thein, Swee Lay ;

Goodall, Alison H. ;

Spector, Tim D. ;

Deloukas, Panos ;

Ouwehand, Willem H. .

BLOOD, 2009, 113 (16) :3831-3837

[73] Endocytosis and storage of plasma factor V by human megakaryocytes [J].

Suehiro, Y ;

Veljkovic, DK ;

Fuller, N ;

Motomura, Y ;

Massé, JM ;

Cramer, EM ;

Hayward, CPM .

THROMBOSIS AND HAEMOSTASIS, 2005, 94 (03) :585-592

[74] PANTHER: A library of protein families and subfamilies indexed by function [J].

Thomas, PD ;

Campbell, MJ ;

Kejariwal, A ;

Mi, HY ;

Karlak, B ;

Daverman, R ;

Diemer, K ;

Muruganujan, A ;

Narechania, A .

GENOME RESEARCH, 2003, 13 (09) :2129-2141

[75] Cytoskeletal mechanics of proplatelet maturation and platelet release [J].

Thon, Jonathan N. ;

Montalvo, Alejandro ;

Patel-Hett, Sunita ;

Devine, Matthew T. ;

Richardson, Jennifer L. ;

Ehrlicher, Allen ;

Larson, Mark K. ;

Hoffmeister, Karin ;

Hartwig, John H. ;

Italiano, Joseph E., Jr. .

JOURNAL OF CELL BIOLOGY, 2010, 191 (04) :861-874

[76] Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes [J].

Todd, John A. ;

Walker, Neil M. ;

Cooper, Jason D. ;

Smyth, Deborah J. ;

Downes, Kate ;

Plagnol, Vincent ;

Bailey, Rebecca ;

Nejentsev, Sergey ;

Field, Sarah F. ;

Payne, Felicity ;

Lowe, Christopher E. ;

Szeszko, Jeffrey S. ;

Hafler, Jason P. ;

Zeitels, Lauren ;

Yang, Jennie H. M. ;

Vella, Adrian ;

Nutland, Sarah ;

Stevens, Helen E. ;

Schuilenburg, Helen ;

Coleman, Gillian ;

Maisuria, Meeta ;

Meadows, William ;

Smink, Luc J. ;

Healy, Barry ;

Burren, Oliver S. ;

Lam, Alex A. C. ;

Ovington, Nigel R. ;

Allen, James ;

Adlem, Ellen ;

Leung, Hin-Tak ;

Wallace, Chris ;

Howson, Joanna M. M. ;

Guja, Cristian ;

Ionescu-Tirgoviste, Constantin ;

Simmonds, Matthew J. ;

Heward, Joanne M. ;

Gough, Stephen C. L. ;

Dunger, David B. ;

Wicker, Linda S. ;

Clayton, David G. .

NATURE GENETICS, 2007, 39 (07) :857-864

[77] Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways [J].

Tong, W ;

Zhang, J ;

Lodish, HF .

BLOOD, 2005, 105 (12) :4604-4612

[78] Chromatin marks identify critical cell types for fine mapping complex trait variants [J].

Trynka, Gosia ;

Sandor, Cynthia ;

Han, Buhm ;

Xu, Han ;

Stranger, Barbara E. ;

Liu, X. Shirley ;

Raychaudhuri, Soumya .

NATURE GENETICS, 2013, 45 (02) :124-130

[79]

Turner S, 2011, QUALITY CONTROL PROC

[80] The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells [J].

Wahlberg, Karin ;

Jiang, Jie ;

Rooks, Helen ;

Jawaid, Kiran ;

Matsuda, Fumihiko ;

Yamaguchi, Masao ;

Lathrop, Mark ;

Thein, Swee Lay ;

Best, Steve .

BLOOD, 2009, 114 (06) :1254-1262

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