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Human Genetics

, Volume 133, Issue 1, pp 95–109 | Cite as

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

  • Khader Shameer
  • Joshua C. Denny
  • Keyue Ding
  • Hayan Jouni
  • David R. Crosslin
  • Mariza de Andrade
  • Christopher G. Chute
  • Peggy Peissig
  • Jennifer A. Pacheco
  • Rongling Li
  • Lisa Bastarache
  • Abel N. Kho
  • Marylyn D. Ritchie
  • Daniel R. Masys
  • Rex L. Chisholm
  • Eric B. Larson
  • Catherine A. McCarty
  • Dan M. Roden
  • Gail P. Jarvik
  • Iftikhar J. KulloEmail author
Original Investigation

Abstract

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 (α: 0.05/56 = 9E−4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 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.

Keywords

Enrichment Analysis Mean Platelet Volume European Ancestry Disease Ontology Term Enrichment Analysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The eMERGE network was initiated and funded by the National Human Genome Research Institute (NHGR1), with additional funding from National Institute of General Medical Sciences (NIGMS) through the following grants: U01-HG-04599 (Mayo Clinic); U01-HG-004610 and UO1-AG-06781 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01HG004609 (Northwestern University); and U01-HG-04603 (Vanderbilt University, also serving as the Administrative Coordinating Center). We also acknowledge the genotyping centers U01-HG-004424 (Broad Institute) and U01-HG-004438 (Johns Hopkins University, Center for Inherited Disease Research). Additional genotyping support was provided by a Washington State Life Sciences Discovery Fund award to the Northwest Institute of Genetic Medicine (G.P.J). Additional support for PheWAS was provided through R01-LM-010685.

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

439_2013_1355_MOESM1_ESM.pdf (967 kb)
Supplementary material 1 (PDF 967 kb)

References

  1. Alcina A, Vandenbroeck K, Otaegui D, Saiz A, Gonzalez JR, Fernandez O, Cavanillas ML, Cenit MC, Arroyo R, Alloza I et al (2010) The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis. Genes Immun 11:439–445PubMedCrossRefGoogle Scholar
  2. Behrends C, Sowa ME, Gygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466:68–76PubMedCentralPubMedCrossRefGoogle Scholar
  3. Blair P, Flaumenhaft R (2009) Platelet alpha-granules: basic biology and clinical correlates. Blood Rev 23:177–189PubMedCentralPubMedCrossRefGoogle Scholar
  4. Blattmann P, Schuberth C, Pepperkok R, Runz H (2013) RNAi-based functional profiling of loci from blood lipid genome-wide association studies identifies genes with cholesterol-regulatory function. PLoS Genet 9:e1003338PubMedCentralPubMedCrossRefGoogle Scholar
  5. Cameron HA, Phillips R, Ibbotson RM, Carson PH (1983) Platelet size in myocardial infarction. Br Med J (Clin Res Ed) 287:449–451CrossRefGoogle Scholar
  6. Daly ME (2011) Determinants of platelet count in humans. Haematologica 96:10–13PubMedCrossRefGoogle Scholar
  7. del Zoppo GJ (1998) The role of platelets in ischemic stroke. Neurology 51:S9–S14PubMedCrossRefGoogle Scholar
  8. Denny JC, Ritchie MD, Basford MA, Pulley JM, Bastarache L, Brown-Gentry K, Wang D, Masys DR, Roden DM, Crawford DC (2010) PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics 26:1205–1210PubMedCrossRefGoogle Scholar
  9. Denny JC, Crawford DC, Ritchie MD, Bielinski SJ, Basford MA, Bradford Y, Chai HS, Bastarache L, Zuvich R, Peissig P et al (2011) Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. Am J Hum Genet 89:529–542PubMedCentralPubMedCrossRefGoogle Scholar
  10. Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ (2000) Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 113(Pt 19):3365–3374PubMedGoogle Scholar
  11. Dhar A, Shukla SD (1993) Tyrosine kinases in platelet signalling. Br J Haematol 84:1–7PubMedCrossRefGoogle Scholar
  12. Du P, Feng G, Flatow J, Song J, Holko M, Kibbe WA, Lin SM (2009) From disease ontology to disease-ontology lite: statistical methods to adapt a general-purpose ontology for the test of gene-ontology associations. Bioinformatics 25:i63–i68PubMedCrossRefGoogle Scholar
  13. Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ et al (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103–109PubMedCrossRefGoogle Scholar
  14. Eriksson N, Tung JY, Kiefer AK, Hinds DA, Francke U, Mountain JL, Do CB (2012) Novel associations for hypothyroidism include known autoimmune risk Loci. PLoS One 7:e34442PubMedCentralPubMedCrossRefGoogle Scholar
  15. Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, Oppermann U, Dilthey A, Pirinen M, Stone MA et al (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761–767PubMedCentralPubMedCrossRefGoogle Scholar
  16. Ferreira MA, Hottenga JJ, Warrington NM, Medland SE, Willemsen G, Lawrence RW, Gordon S, de Geus EJ, Henders AK, Smit JH et al (2009) Sequence variants in three loci influence monocyte counts and erythrocyte volume. Am J Hum Genet 85:745–749PubMedCentralPubMedCrossRefGoogle Scholar
  17. Fitzgerald DJ (1999) Fibrinogen receptor and platelet signalling. Blood Coagul Fibrinolysis 10(Suppl 1):S77–S79PubMedGoogle Scholar
  18. Flaumenhaft R (2003) Molecular basis of platelet granule secretion. Arterioscler Thromb Vasc Biol 23:1152–1160PubMedCrossRefGoogle Scholar
  19. Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115:3378–3384PubMedCentralPubMedCrossRefGoogle Scholar
  20. Gay LJ, Felding-Habermann B (2011a) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11:123–134PubMedCrossRefGoogle Scholar
  21. Gay LJ, Felding-Habermann B (2011b) Platelets alter tumor cell attributes to propel metastasis: programming in transit. Cancer Cell 20:553–554PubMedCrossRefGoogle Scholar
  22. Gibbins JM (2004) Platelet adhesion signalling and the regulation of thrombus formation. J Cell Sci 117:3415–3425PubMedCrossRefGoogle Scholar
  23. Gieger C, Radhakrishnan A, Cvejic A, Tang W, Porcu E, Pistis G, Serbanovic-Canic J, Elling U, Goodall AH, Labrune Y et al (2011) New gene functions in megakaryopoiesis and platelet formation. Nature 480(7376):201–208. doi: 10.1038/nature10659 Google Scholar
  24. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H et al (2009) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41:342–347PubMedCrossRefGoogle Scholar
  25. Hebbring SJ, Schrodi SJ, Ye Z, Zhou Z, Page D, Brilliant MH (2013) A PheWAS approach in studying HLA-DRB1*1501. Genes Immun 14:187–191PubMedCentralPubMedCrossRefGoogle Scholar
  26. Hinks A, Martin P, Flynn E, Eyre S, Packham J, Barton A, Worthington J, Thomson W (2010) Investigation of type 1 diabetes and coeliac disease susceptibility loci for association with juvenile idiopathic arthritis. Ann Rheum Dis 69:2169–2172PubMedCentralPubMedCrossRefGoogle Scholar
  27. Honn KV, Tang DG, Crissman JD (1992) Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev 11:325–351PubMedCrossRefGoogle Scholar
  28. Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, Romanos J, Dinesen LC, Ryan AW, Panesar D et al (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40:395–402PubMedCentralPubMedCrossRefGoogle Scholar
  29. Huo Y, Ley KF (2004) Role of platelets in the development of atherosclerosis. Trends Cardiovasc Med 14:18–22PubMedCrossRefGoogle Scholar
  30. Italiano JE Jr, Lecine P, Shivdasani RA, Hartwig JH (1999) Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. J Cell Biol 147:1299–1312PubMedCrossRefGoogle Scholar
  31. Johnson AD (2011) The genetics of common variation affecting platelet development, function and pharmaceutical targeting. J Thromb Haemost 9(Suppl 1):246–257PubMedCentralPubMedCrossRefGoogle Scholar
  32. Kamatani Y, Matsuda K, Okada Y, Kubo M, Hosono N, Daigo Y, Nakamura Y, Kamatani N (2010) Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 42:210–215PubMedCrossRefGoogle Scholar
  33. Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB, Sabatti C, Eskin E (2010) Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42:348–354PubMedCentralPubMedCrossRefGoogle Scholar
  34. Kaplan JE, Saba TM (1978) Platelet removal from the circulation by the liver and spleen. Am J Physiol 235:H314–H320PubMedGoogle Scholar
  35. Kisacik B, Tufan A, Kalyoncu U, Karadag O, Akdogan A, Ozturk MA, Kiraz S, Ertenli I, Calguneri M (2008) Mean platelet volume (MPV) as an inflammatory marker in ankylosing spondylitis and rheumatoid arthritis. Jt Bone Spine 75:291–294CrossRefGoogle Scholar
  36. Kottke-Marchant K (2009) Importance of platelets and platelet response in acute coronary syndromes. Cleve Clin J Med 76(Suppl 1):S2–S7PubMedCrossRefGoogle Scholar
  37. Kullo IJ, Ding K, Jouni H, Smith CY, Chute CG (2010) A genome-wide association study of red blood cell traits using the electronic medical record. PLoS One 5(9). pii:e13011. doi: 10.1371/journal.pone.0013011
  38. Kunicki TJ, Nugent DJ (2010) The genetics of normal platelet reactivity. Blood 116:2627–2634PubMedCrossRefGoogle Scholar
  39. Kunicki TJ, Williams SA, Salomon DR, Harrison P, Crisler P, Nakagawa P, Mondala TS, Head SR, Nugent DJ (2009) Genetics of platelet reactivity in normal, healthy individuals. J Thromb Haemost 7:2116–2122PubMedCrossRefGoogle Scholar
  40. Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20:576–590PubMedCentralPubMedCrossRefGoogle Scholar
  41. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T et al (2009) Genome-wide association study of blood pressure and hypertension. Nat Genet 41:677–687PubMedCentralPubMedCrossRefGoogle Scholar
  42. Levy-Toledano S (1999) Platelet signal transduction pathways: could we organize them into a ‘hierarchy’? Haemostasis 29:4–15PubMedGoogle Scholar
  43. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010a) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834PubMedCentralPubMedCrossRefGoogle Scholar
  44. Li Z, Delaney MK, O’Brien KA, Du X (2010b) Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol 30:2341–2349PubMedCentralPubMedCrossRefGoogle Scholar
  45. Mahaney MC, Brugnara C, Lease LR, Platt OS (2005) Genetic influences on peripheral blood cell counts: a study in baboons. Blood 106:1210–1214PubMedCrossRefGoogle Scholar
  46. Matthews L, Gopinath G, Gillespie M, Caudy M, Croft D, de Bono B, Garapati P, Hemish J, Hermjakob H, Jassal B et al (2009) Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Res 37:D619–D622PubMedCentralPubMedCrossRefGoogle Scholar
  47. McBane RD 2nd, Karnicki K, Miller RS, Owen WG (2004) The impact of peripheral arterial disease on circulating platelets. Thromb Res 113:137–145PubMedCrossRefGoogle Scholar
  48. McCarty CA, Chisholm RL, Chute CG, Kullo IJ, Jarvik GP, Larson EB, Li R, Masys DR, Ritchie MD, Roden DM et al (2011) The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies. BMC Med Genomics 4:13PubMedCentralPubMedCrossRefGoogle Scholar
  49. Meisinger C, Prokisch H, Gieger C, Soranzo N, Mehta D, Rosskopf D, Lichtner P, Klopp N, Stephens J, Watkins NA et al (2009) A genome-wide association study identifies three loci associated with mean platelet volume. Am J Hum Genet 84:66–71PubMedCentralPubMedCrossRefGoogle Scholar
  50. Menzel S, Jiang J, Silver N, Gallagher J, Cunningham J, Surdulescu G, Lathrop M, Farrall M, Spector TD, Thein SL (2007) The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood 110:3624–3626PubMedCrossRefGoogle Scholar
  51. Movat HZ, Weiser WJ, Glynn MF, Mustard JF (1965) Platelet phagocytosis and aggregation. J Cell Biol 27:531–543PubMedCrossRefGoogle Scholar
  52. Nachman RL, Rafii S (2008) Platelets, petechiae, and preservation of the vascular wall. N Engl J Med 359:1261–1270PubMedCentralPubMedCrossRefGoogle Scholar
  53. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S et al (2009) Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 41:666–676PubMedCentralPubMedCrossRefGoogle Scholar
  54. O’Donnell CJ, Larson MG, Feng D, Sutherland PA, Lindpaintner K, Myers RH, D’Agostino RA, Levy D, Tofler GH (2001) Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation 103:3051–3056PubMedCrossRefGoogle Scholar
  55. Pain A, Ferguson DJ, Kai O, Urban BC, Lowe B, Marsh K, Roberts DJ (2001) Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc Natl Acad Sci USA 98:1805–1810PubMedCrossRefGoogle Scholar
  56. Patel SR, Hartwig JH, Italiano JE Jr (2005) The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest 115:3348–3354PubMedCentralPubMedCrossRefGoogle Scholar
  57. Paul DS, Nisbet JP, Yang TP, Meacham S, Rendon A, Hautaviita K, Tallila J, White J, Tijssen MR, Sivapalaratnam S et al (2011) Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits. PLoS Genet 7:e1002139PubMedCentralPubMedCrossRefGoogle Scholar
  58. Pendergrass SA, Brown-Gentry K, Dudek SM, Torstenson ES, Ambite JL, Avery CL, Buyske S, Cai C, Fesinmeyer MD, Haiman C et al (2011) The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery. Genet Epidemiol 35:410–422PubMedCentralPubMedCrossRefGoogle Scholar
  59. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26:2336–2337PubMedCrossRefGoogle Scholar
  60. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCentralPubMedCrossRefGoogle Scholar
  61. Qayyum R, Snively BM, Ziv E, Nalls MA, Liu Y, Tang W, Yanek LR, Lange L, Evans MK, Ganesh S et al (2012) A meta-analysis and genome-wide association study of platelet count and mean platelet volume in African Americans. PLoS Genet 8:e1002491PubMedCentralPubMedCrossRefGoogle Scholar
  62. Qiao JL, Shen Y, Gardiner EE, Andrews RK (2010) Proteolysis of platelet receptors in humans and other species. Biol Chem 391:893–900PubMedCrossRefGoogle Scholar
  63. Raychaudhuri S (2011) Mapping rare and common causal alleles for complex human diseases. Cell 147:57–69PubMedCentralPubMedCrossRefGoogle Scholar
  64. Reed GL (2004) Platelet secretory mechanisms. Semin Thromb Hemost 30:441–450PubMedCrossRefGoogle Scholar
  65. Richardson JL, Shivdasani RA, Boers C, Hartwig JH, Italiano JE Jr (2005) Mechanisms of organelle transport and capture along proplatelets during platelet production. Blood 106:4066–4075PubMedCrossRefGoogle Scholar
  66. Ripatti S, Tikkanen E, Orho-Melander M, Havulinna AS, Silander K, Sharma A, Guiducci C, Perola M, Jula A, Sinisalo J et al (2010) A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376:1393–1400PubMedCentralPubMedCrossRefGoogle Scholar
  67. Ritchie MD, Denny JC, Zuvich RL, Crawford DC, Schildcrout JS, Bastarache L, Ramirez AH, Mosley JD, Pulley JM, Basford MA et al (2013) Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. Circulation 127:1377–1385PubMedCrossRefGoogle Scholar
  68. Saade S, Cazier JB, Ghassibe-Sabbagh M, Youhanna S, Badro DA, Kamatani Y, Hager J, Yeretzian JS, El-Khazen G, Haber M et al (2011) Large scale association analysis identifies three susceptibility loci for coronary artery disease. PLoS One 6:e29427PubMedCentralPubMedCrossRefGoogle Scholar
  69. Schaub MA, Boyle AP, Kundaje A, Batzoglou S, Snyder M (2012) Linking disease associations with regulatory information in the human genome. Genome Res 22:1748–1759PubMedCrossRefGoogle Scholar
  70. Schulze H, Korpal M, Bergmeier W, Italiano JE Jr, Wahl SM, Shivdasani RA (2004) Interactions between the megakaryocyte/platelet-specific beta1 tubulin and the secretory leukocyte protease inhibitor SLPI suggest a role for regulated proteolysis in platelet functions. Blood 104:3949–3957PubMedCrossRefGoogle Scholar
  71. Smyth SS, McEver RP, Weyrich AS, Morrell CN, Hoffman MR, Arepally GM, French PA, Dauerman HL, Becker RC (2009) Platelet functions beyond hemostasis. J Thromb Haemost 7:1759–1766PubMedCrossRefGoogle Scholar
  72. Soranzo N, Spector TD, Mangino M, Kuhnel B, Rendon A, Teumer A, Willenborg C, Wright B, Chen L, Li M et al (2009a) A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41:1182–1190PubMedCentralPubMedCrossRefGoogle Scholar
  73. Soranzo N, Rendon A, Gieger C, Jones CI, Watkins NA, Menzel S, Doring A, Stephens J, Prokisch H, Erber W et al (2009b) A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. Blood 113:3831–3837PubMedCentralPubMedCrossRefGoogle Scholar
  74. Suehiro Y, Veljkovic DK, Fuller N, Motomura Y, Masse JM, Cramer EM, Hayward CP (2005) Endocytosis and storage of plasma factor V by human megakaryocytes. Thromb Haemost 94:585–592PubMedGoogle Scholar
  75. Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, Diemer K, Muruganujan A, Narechania A (2003) PANTHER: a library of protein families and subfamilies indexed by function. Genome Res 13:2129–2141PubMedCrossRefGoogle Scholar
  76. Thon JN, Montalvo A, Patel-Hett S, Devine MT, Richardson JL, Ehrlicher A, Larson MK, Hoffmeister K, Hartwig JH, Italiano JE Jr (2010) Cytoskeletal mechanics of proplatelet maturation and platelet release. J Cell Biol 191:861–874PubMedCrossRefGoogle Scholar
  77. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, Bailey R, Nejentsev S, Field SF, Payne F et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39:857–864PubMedCentralPubMedCrossRefGoogle Scholar
  78. Tong W, Zhang J, Lodish HF (2005) Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Blood 105:4604–4612PubMedCrossRefGoogle Scholar
  79. Trynka G, Sandor C, Han B, Xu H, Stranger BE, Liu XS, Raychaudhuri S (2013) Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet 45:124–130PubMedCrossRefGoogle Scholar
  80. Turner S, Armstrong LL, Bradford Y, Carlson CS, Crawford DC, Crenshaw AT, de Andrade M, Doheny KF, Haines JL, Hayes G et al (2011) Quality control procedures for genome-wide association studies. Current protocols in human genetics/editorial board, Jonathan L. Haines… [et al.], Chapter 1, Unit1 19Google Scholar
  81. Wahlberg K, Jiang J, Rooks H, Jawaid K, Matsuda F, Yamaguchi M, Lathrop M, Thein SL, Best S (2009) The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells. Blood 114:1254–1262PubMedCrossRefGoogle Scholar
  82. Wang DS, Shaw G (1995) The association of the C-terminal region of beta I sigma II spectrin to brain membranes is mediated by a PH domain, does not require membrane proteins, and coincides with a inositol-1,4,5 triphosphate binding site. Biochem Biophys Res Commun 217:608–615PubMedCrossRefGoogle Scholar
  83. Watkins NA, Gusnanto A, de Bono B, De S, Miranda-Saavedra D, Hardie DL, Angenent WG, Attwood AP, Ellis PD, Erber W et al (2009) A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood 113:e1–e9PubMedCrossRefGoogle Scholar
  84. Weber C (2005) Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 96:612–616PubMedCrossRefGoogle Scholar
  85. Willoughby S, Holmes A, Loscalzo J (2002) Platelets and cardiovascular disease. Eur J Cardiovasc Nurs 1:273–288PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Khader Shameer
    • 1
  • Joshua C. Denny
    • 2
  • Keyue Ding
    • 1
  • Hayan Jouni
    • 1
  • David R. Crosslin
    • 3
  • Mariza de Andrade
    • 4
  • Christopher G. Chute
    • 4
  • Peggy Peissig
    • 5
  • Jennifer A. Pacheco
    • 6
  • Rongling Li
    • 7
  • Lisa Bastarache
    • 2
  • Abel N. Kho
    • 8
  • Marylyn D. Ritchie
    • 9
  • Daniel R. Masys
    • 10
  • Rex L. Chisholm
    • 6
  • Eric B. Larson
    • 11
  • Catherine A. McCarty
    • 12
  • Dan M. Roden
    • 13
  • Gail P. Jarvik
    • 14
  • Iftikhar J. Kullo
    • 1
    Email author
  1. 1.Division of Cardiovascular DiseasesMayo ClinicRochesterUSA
  2. 2.Departments of Medicine and Biomedical InformaticsVanderbilt UniversityNashvilleUSA
  3. 3.Department of BiostatisticsUniversity of WashingtonSeattleUSA
  4. 4.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  5. 5.Biomedical Informatics Research CenterMarshfield ClinicMarshfieldUSA
  6. 6.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  7. 7.Office of Population GenomicsNational Human Genome Research InstituteBethesdaUSA
  8. 8.Department of MedicineNorthwestern UniversityChicagoUSA
  9. 9.Center for Systems Genomics, The Huck Institutes of the Life Sciences, Eberly College of SciencePennsylvania State UniversityUniversity ParkUSA
  10. 10.Department of Biomedical InformaticsVanderbilt University School of MedicineNashvilleUSA
  11. 11.Group Health Research InstituteSeattleUSA
  12. 12.Essentia Institute of Rural HealthDuluthUSA
  13. 13.Department of PharmacologyVanderbilt University School of MedicineNashvilleUSA
  14. 14.Department of Genome SciencesUniversity of WashingtonSeattleUSA

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