Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

American Journal of Human Genetics

Volumn 99, Issue 1, 2016, Pages 22-39

  Tajuddin, Salman M ^a   Schick, Ursula M ^b   Eicher, John D ^c   Chami, Nathalie ^d,e   Giri, Ayush ^f   Brody, Jennifer A ^g   Hill, W David ^h   Kacprowski, Tim ^i,j   Li, Jin ^k   Lyytikäinen, Leo Pekka ^l,m   Manichaikul, Ani ⁿ   Mihailov, Evelin ^o   O'Donoghue, Michelle L ^p   Pankratz, Nathan ^q   Pazoki, Raha ^r   Polfus, Linda M ^s   Smith, Albert Vernon ^t,u   Schurmann, Claudia ^b   Vacchi Suzzi, Caterina ^v   Waterworth, Dawn M ^w   Evangelou, Evangelos ^x,y   Yanek, Lisa R ^z   Burt, Amber ^aa   Chen, Ming Huei ^c   van Rooij, Frank J A ^r   Floyd, James S ^g   Greinacher, Andreas ^ab   Harris, Tamara B ^a   Highland, Heather M ^s,ac   Lange, Leslie A ^ad   Liu, Yongmei ^ae   Mägi, Reedik ^o   Nalls, Mike A ^a   Mathias, Rasika A ^z   Nickerson, Deborah A ^aa   Nikus, Kjell ^m,af   Starr, John M ^h   Tardif, Jean Claude ^d,e   Tzoulaki, Ioanna ^x,y   Velez Edwards, Digna R ^ag   Wallentin, Lars ^ah   Bartz, Traci M ^g   Becker, Lewis C ^z   Denny, Joshua C ^ag   Raffield, Laura M ^ad   Rioux, John D ^d,e   Friedrich, Nele ^j,ab   Fornage, Myriam ^ai   Gao, He ^x   Hirschhorn, Joel N ^aj,ak   Liewald, David C M ^h   Rich, Stephen S ⁿ   Uitterlinden, Andre ^r,al   Bastarache, Lisa ^ag   Becker, Diane M ^z   Boerwinkle, Eric ^s,am   de Denus, Simon ^d,e   Bottinger, Erwin P ^b   Hayward, Caroline ^an   Hofman, Albert ^r,ao   Homuth, Georg ⁱ   Lange, Ethan ^ac   Launer, Lenore J ^a   Lehtimäki, Terho ^l,m   Lu, Yingchang ^b   Metspalu, Andres ^o   O'Donnell, Chris J ^c,ap   Quarells, Rakale C ^aq   Richard, Melissa ^ai   Torstenson, Eric S ^f   Taylor, Kent D ^ar,as   Vergnaud, Anne Claire ^x   Zonderman, Alan B ^a   Crosslin, David R ^g   Deary, Ian J ^h   Dörr, Marcus ^j,ab   Elliott, Paul ^x   Evans, Michele K ^a   Gudnason, Vilmundur ^t,u   Kähönen, Mika ^m,af   Psaty, Bruce M ^aa,at   Rotter, Jerome I ^ar,as   Slater, Andrew J ^w,au   Dehghan, Abbas ^r   White, Harvey D ^av   Ganesh, Santhi K ^aw   Loos, Ruth J F ^b   Esko, Tõnu ^o,aj   Faraday, Nauder ^z   Wilson, James G ^ax   Cushman, Mary ^ay   Johnson, Andrew D ^c   Edwards, Todd L ^ag   Zakai, Neil A ^ay   Lettre, Guillaume ^d,e   Reiner, Alex P ^g,az   Auer, Paul L ^ba   more..

^a NATIONAL INSTITUTE ON AGING   (United States)

^b MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^c FRAMINGHAM HEART STUDY   (United States)

^d UNIVERSITÉ DE MONTRÉAL   (Canada)

^e MONTREAL HEART INSTITUTE   (Canada)

^f VANDERBILT UNIVERSITY   (United States)

^g UNIVERSITY OF WASHINGTON   (United States)

^h UNIVERSITY OF EDINBURGH   (United Kingdom)

ⁱ UNIVERSITY OF GREIFSWALD   (Germany)

^j DZHK GERMAN CENTRE FOR CARDIOVASCULAR RESEARCH   (Germany)

^k STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^l FIMLAB LABORATORIES   (Finland)

^m TAMPERE UNIVERSITY OF TECHNOLOGY   (Finland)

ⁿ UNIVERSITY OF VIRGINIA   (United States)

^o UNIVERSITY OF TARTU   (Estonia)

^p BRIGHAM AND WOMEN S HOSPITAL   (United States)

^q UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

^r ERASMUS MEDICAL CENTER   (Netherlands)

^s UNIVERSITY OF TEXAS SCHOOL OF PUBLIC HEALTH   (United States)

^t ICELANDIC HEART ASSOCIATION   (Iceland)

^u UNIVERSITY OF ICELAND   (Iceland)

^v STONY BROOK UNIVERSITY   (United States)

^w GLAXOSMITHKLINE   (United States)

^x IMPERIAL COLLEGE LONDON   (United Kingdom)

^y UNIVERSITY OF IOANNINA   (Greece)

^z JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^aa UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^ab UNIVERSITY MEDICINE GREIFSWALD   (Germany)

^ac IL   (United States)

^ad UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^ae WAKE FOREST SCHOOL OF MEDICINE   (United States)

^af TAMPERE UNIVERSITY HOSPITAL   (Finland)

^ag VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^ah UPPSALA UNIVERSITY   (Sweden)

^ai UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^aj BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^ak BOSTON CHILDREN S HOSPITAL   (United States)

^al Netherlands Consortium for Healthy Aging   (Netherlands)

^am BAYLOR COLLEGE OF MEDICINE   (United States)

^an UNIVERSITY OF EDINBURGH   (United Kingdom)

^ao HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^ap Boston Veterans Administration (VA) Health Care System   (United States)

^aq MOREHOUSE SCHOOL OF MEDICINE   (United States)

^ar LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE   (United States)

^as HARBOR UCLA MEDICAL CENTER   (United States)

^at CENTER FOR HEALTH STUDIES   (United States)

^au Omicsoft Corp   (United States)

^av AUCKLAND CITY HOSPITAL   (New Zealand)

^aw UNIVERSITY OF MICHIGAN   (United States)

^ax UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

^ay UNIVERSITY OF VERMONT COLLEGE OF MEDICINE   (United States)

^az Fred Hutchinson Cancer Research Center   (United States)

^ba UNIVERSITY OF WISCONSIN MILWAUKEE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

CD33 ANTIGEN; CD69 ANTIGEN; TRANSCRIPTION FACTOR; UROKINASE RECEPTOR;

3' UNTRANSLATED REGION; AFRICAN; ARTICLE; AUTOIMMUNE DISEASE; BASOPHIL; CELL DIFFERENTIATION; CYTOPENIA; EAST ASIAN; EOSINOPHIL COUNT; EUROPEAN; EXOME; GENE IDENTIFICATION; GENE LOCUS; GENE MUTATION; GENE REPLICATION; GENOME-WIDE ASSOCIATION STUDY; GENOTYPING TECHNIQUE; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HISPANIC; HUMAN; LEUKOCYTE; LEUKOCYTE COUNT; LYMPHOCYTE COUNT; LYMPHOID PROGENITOR CELL; MAJOR CLINICAL STUDY; MONOCYTE; MYELOID PROGENITOR CELL; NEUTROPHIL COUNT; PHENOTYPIC VARIATION; PLEIOTROPY; PRIORITY JOURNAL; SOUTH ASIAN; BLOOD CELL COUNT; CYTOLOGY; GENETICS; IMMUNOPATHOLOGY; META ANALYSIS; QUALITY CONTROL;

BLOOD CELL COUNT; EXOME; GENETIC LOCI; GENETIC PLEIOTROPY; GENOME-WIDE ASSOCIATION STUDY; HUMANS; IMMUNE SYSTEM DISEASES; LEUKOCYTES; QUALITY CONTROL;

EID: 84989906739     PISSN: 00029297     EISSN: 15376605     Source Type: Journal    
DOI: 10.1016/j.ajhg.2016.05.003     Document Type: Article

References (96)

1. 1 Chen, L., Kostadima, M., Martens, J.H., Canu, G., Garcia, S.P., Turro, E., Downes, K., Macaulay, I.C., Bielczyk-Maczynska, E., Coe, S., et al., BRIDGE Consortium. Transcriptional diversity during lineage commitment of human blood progenitors. Science, 345, 2014, 1251033.
2. 2 Gasteiger, G., Rudensky, A.Y., Interactions between innate and adaptive lymphocytes. Nat. Rev. Immunol. 14 (2014), 631–639.
3. 3 Reiner, A.P., Lettre, G., Nalls, M.A., Ganesh, S.K., Mathias, R., Austin, M.A., Dean, E., Arepalli, S., Britton, A., Chen, Z., et al. Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT). PLoS Genet., 7, 2011, e1002108.
4. 4 Kong, M., Lee, C., Genetic associations with C-reactive protein level and white blood cell count in the KARE study. Int. J. Immunogenet. 40 (2013), 120–125.
5. 5 Crosslin, D.R., McDavid, A., Weston, N., Nelson, S.C., Zheng, X., Hart, E., de Andrade, M., Kullo, I.J., McCarty, C.A., Doheny, K.F., et al., Electronic Medical Records and Genomics (eMERGE) Network. Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network. Hum. Genet. 131 (2012), 639–652.
6. 6 Nalls, M.A., Couper, D.J., Tanaka, T., van Rooij, F.J., Chen, M.H., Smith, A.V., Toniolo, D., Zakai, N.A., Yang, Q., Greinacher, A., et al. Multiple loci are associated with white blood cell phenotypes. PLoS Genet., 7, 2011, e1002113.
7. 7 Kamatani, Y., Matsuda, K., Okada, Y., Kubo, M., Hosono, N., Daigo, Y., Nakamura, Y., Kamatani, N., Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat. Genet. 42 (2010), 210–215.
8. 8 Keller, M.F., Reiner, A.P., Okada, Y., van Rooij, F.J., Johnson, A.D., Chen, M.H., Smith, A.V., Morris, A.P., Tanaka, T., Ferrucci, L., et al. CHARGE Hematology COGENT, BioBank Japan Project (RIKEN) Working Groups. Trans-ethnic meta-analysis of white blood cell phenotypes. Hum. Mol. Genet. 23 (2014), 6944–6960.
9. 9 Soranzo, N., Spector, T.D., Mangino, M., Kühnel, B., Rendon, A., Teumer, A., Willenborg, C., Wright, B., Chen, L., Li, M., et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat. Genet. 41 (2009), 1182–1190.
10. 10 Li, J., Glessner, J.T., Zhang, H., Hou, C., Wei, Z., Bradfield, J.P., Mentch, F.D., Guo, Y., Kim, C., Xia, Q., et al. GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children. Hum. Mol. Genet. 22 (2013), 1457–1464.
11. 11 Auer, P.L., Johnsen, J.M., Johnson, A.D., Logsdon, B.A., Lange, L.A., Nalls, M.A., Zhang, G., Franceschini, N., Fox, K., Lange, E.M., et al. Imputation of exome sequence variants into population- based samples and blood-cell-trait-associated loci in African Americans: NHLBI GO Exome Sequencing Project. Am. J. Hum. Genet. 91 (2012), 794–808.
12. 12 Auer, P.L., Teumer, A., Schick, U., O'Shaughnessy, A., Lo, K.S., Chami, N., Carlson, C., de Denus, S., Dubé, M.P., Haessler, J., et al. Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat. Genet. 46 (2014), 629–634.
13. 13 Nalls, M.A., Wilson, J.G., Patterson, N.J., Tandon, A., Zmuda, J.M., Huntsman, S., Garcia, M., Hu, D., Li, R., Beamer, B.A., et al. Admixture mapping of white cell count: genetic locus responsible for lower white blood cell count in the Health ABC and Jackson Heart studies. Am. J. Hum. Genet. 82 (2008), 81–87.
14. 14 Grove, M.L., Yu, B., Cochran, B.J., Haritunians, T., Bis, J.C., Taylor, K.D., Hansen, M., Borecki, I.B., Cupples, L.A., Fornage, M., et al. Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. PLoS ONE, 8, 2013, e68095.
15. 15 Winkler, T.W., Day, F.R., Croteau-Chonka, D.C., Wood, A.R., Locke, A.E., Mägi, R., Ferreira, T., Fall, T., Graff, M., Justice, A.E., et al., Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Quality control and conduct of genome-wide association meta-analyses. Nat. Protoc. 9 (2014), 1192–1212.
16. 16 Auer, P.L., Reiner, A.P., Leal, S.M., The effect of phenotypic outliers and non-normality on rare-variant association testing. Eur. J. Hum. Genet., 2016, 10.1038/ejhg.2015.270 Published online January 6, 2016.
17. 17 Liu, D.J., Peloso, G.M., Zhan, X., Holmen, O.L., Zawistowski, M., Feng, S., Nikpay, M., Auer, P.L., Goel, A., Zhang, H., et al. Meta-analysis of gene-level tests for rare variant association. Nat. Genet. 46 (2014), 200–204.
18. 18 Yang, J., Lee, S.H., Goddard, M.E., Visscher, P.M., GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88 (2011), 76–82.
19. 19 Willer, C.J., Li, Y., Abecasis, G.R., METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 (2010), 2190–2191.
20. 20 Pulley, J., Clayton, E., Bernard, G.R., Roden, D.M., Masys, D.R., Principles of human subjects protections applied in an opt-out, de-identified biobank. Clin. Transl. Sci. 3 (2010), 42–48.
21. 21 Denny, J.C., Bastarache, L., Ritchie, M.D., Carroll, R.J., Zink, R., Mosley, J.D., Field, J.R., Pulley, J.M., Ramirez, A.H., Bowton, E., et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat. Biotechnol. 31 (2013), 1102–1110.
22. 22 Nikpay, M., Goel, A., Won, H.H., Hall, L.M., Willenborg, C., Kanoni, S., Saleheen, D., Kyriakou, T., Nelson, C.P., Hopewell, J.C., et al., CARDIoGRAMplusC4D Consortium. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47 (2015), 1121–1130.
23. 23 Liu, J.Z., van Sommeren, S., Huang, H., Ng, S.C., Alberts, R., Takahashi, A., Ripke, S., Lee, J.C., Jostins, L., Shah, T., et al. International Multiple Sclerosis Genetics Consortium, International IBD Genetics Consortium. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47 (2015), 979–986.
24. 24 Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ohmura, K., Suzuki, A., Yoshida, S., et al. RACI consortium, GARNET consortium. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506 (2014), 376–381.
25. 25 Bentham, J., Morris, D.L., Cunninghame Graham, D.S., Pinder, C.L., Tombleson, P., Behrens, T.W., Martín, J., Fairfax, B.P., Knight, J.C., Chen, L., et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat. Genet. 47 (2015), 1457–1464.
26. 26 Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., et al. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476 (2011), 214–219.
27. 27 Tsoi, L.C., Spain, S.L., Knight, J., Ellinghaus, E., Stuart, P.E., Capon, F., Ding, J., Li, Y., Tejasvi, T., Gudjonsson, J.E., et al. Collaborative Association Study of Psoriasis (CASP) Genetic Analysis of Psoriasis Consortium Psoriasis Association Genetics Extension, Wellcome Trust Case Control Consortium 2. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat. Genet. 44 (2012), 1341–1348.
28. 28 Bradfield, J.P., Qu, H.Q., Wang, K., Zhang, H., Sleiman, P.M., Kim, C.E., Mentch, F.D., Qiu, H., Glessner, J.T., Thomas, K.A., et al. A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet., 7, 2011, e1002293.
29. 29 Dubois, P.C., Trynka, G., Franke, L., Hunt, K.A., Romanos, J., Curtotti, A., Zhernakova, A., Heap, G.A., Adány, R., Aromaa, A., et al. Multiple common variants for celiac disease influencing immune gene expression. Nat. Genet. 42 (2010), 295–302.
30. 30 Cordell, H.J., Han, Y., Mells, G.F., Li, Y., Hirschfield, G.M., Greene, C.S., Xie, G., Juran, B.D., Zhu, D., Qian, D.C., et al. Canadian-US PBC Consortium Italian PBC Genetics Study Group, UK-PBC Consortium. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat. Commun., 6, 2015, 8019.
31. 31 Leslie, R., O'Donnell, C.J., Johnson, A.D., GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database. Bioinformatics 30 (2014), i185–i194.
32. 32 Chami, N., Chen, M.-H., Slater, A.J., Eicher, J.D., Evangelou, E., Tajuddin, S.M., Love-Gregory, L., Kacprowski, T., Schick, U.M., Nomura, A., et al. Exome genotyping identifies pleiotropic variants associated with red blood cell traits. Am. J. Hum. Genet. 99 (2016), 8–21 this issue.
33. 33 Eicher, J.D., Chami, N., Kacprowski, T., Nomura, A., Chen, M.-H., Yanek, L.R., Tajuddin, S.M., Schick, U.M., Slater, A.J., Pankratz, N., et al. Platelet-related variants identified by exomechip meta-analysis in 157,293 individuals. Am. J. Hum. Genet. 99 (2016), 40–55 this issue.
34. 34 Zhang, X., Gierman, H.J., Levy, D., Plump, A., Dobrin, R., Goring, H.H., Curran, J.E., Johnson, M.P., Blangero, J., Kim, S.K., et al. Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs. BMC Genomics, 15, 2014, 532.
35. 35 Wang, K., Li, M., Hakonarson, H., ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res., 38, 2010, e164.
36. 36 Kircher, M., Witten, D.M., Jain, P., O'Roak, B.J., Cooper, G.M., Shendure, J., A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46 (2014), 310–315.
37. 37 Crosslin, D.R., McDavid, A., Weston, N., Zheng, X., Hart, E., de Andrade, M., Kullo, I.J., McCarty, C.A., Doheny, K.F., Pugh, E., et al. CHARGE Hematology Working Group, electronic Medical Records and Genomics (eMERGE) Network. Genetic variation associated with circulating monocyte count in the eMERGE Network. Hum. Mol. Genet. 22 (2013), 2119–2127.
38. 38 Willer, C.J., Schmidt, E.M., Sengupta, S., Peloso, G.M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., Buchkovich, M.L., Mora, S., et al., Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45 (2013), 1274–1283.
39. 39 Ulyanova, T., Blasioli, J., Woodford-Thomas, T.A., Thomas, M.L., The sialoadhesin CD33 is a myeloid-specific inhibitory receptor. Eur. J. Immunol. 29 (1999), 3440–3449.
40. 40 Malik, M., Chiles, J. 3rd, Xi, H.S., Medway, C., Simpson, J., Potluri, S., Howard, D., Liang, Y., Paumi, C.M., Mukherjee, S., et al. Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia. Hum. Mol. Genet. 24 (2015), 3557–3570.
41. 41 Elghetany, M.T., Patel, J., Martinez, J., Schwab, H., CD87 as a marker for terminal granulocytic maturation: assessment of its expression during granulopoiesis. Cytometry B Clin. Cytom. 51 (2003), 9–13.
42. 42 Nykjaer, A., Møller, B., Todd, R.F. 3rd, Christensen, T., Andreasen, P.A., Gliemann, J., Petersen, C.M., Urokinase receptor. An activation antigen in human T lymphocytes. J. Immunol. 152 (1994), 505–516.
43. 43 Park, Y.J., Liu, G., Tsuruta, Y., Lorne, E., Abraham, E., Participation of the urokinase receptor in neutrophil efferocytosis. Blood 114 (2009), 860–870.
44. 44 Shiow, L.R., Rosen, D.B., Brdicková, N., Xu, Y., An, J., Lanier, L.L., Cyster, J.G., Matloubian, M., CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440 (2006), 540–544.
45. 45 van der Harst, P., Zhang, W., Mateo Leach, I., Rendon, A., Verweij, N., Sehmi, J., Paul, D.S., Elling, U., Allayee, H., Li, X., et al. Seventy-five genetic loci influencing the human red blood cell. Nature 492 (2012), 369–375.
46. 46 Zannettino, A.C., Bühring, H.J., Niutta, S., Watt, S.M., Benton, M.A., Simmons, P.J., The sialomucin CD164 (MGC-24v) is an adhesive glycoprotein expressed by human hematopoietic progenitors and bone marrow stromal cells that serves as a potent negative regulator of hematopoiesis. Blood 92 (1998), 2613–2628.
47. 47 Forde, S., Tye, B.J., Newey, S.E., Roubelakis, M., Smythe, J., McGuckin, C.P., Pettengell, R., Watt, S.M., Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells. Blood 109 (2007), 1825–1833.
48. 48 Ward, L.D., Kellis, M., HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40 (2012), D930–D934.
49. 49 Gelsi-Boyer, V., Trouplin, V., Adélaïde, J., Bonansea, J., Cervera, N., Carbuccia, N., Lagarde, A., Prebet, T., Nezri, M., Sainty, D., et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br. J. Haematol. 145 (2009), 788–800.
50. 50 Watanabe, S., Watanabe, K., Akimov, V., Bartkova, J., Blagoev, B., Lukas, J., Bartek, J., JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks. Nat. Struct. Mol. Biol. 20 (2013), 1425–1433.
51. 51 Johnson, A.D., Yanek, L.R., Chen, M.H., Faraday, N., Larson, M.G., Tofler, G., Lin, S.J., Kraja, A.T., Province, M.A., Yang, Q., et al. Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat. Genet. 42 (2010), 608–613.
52. 52 Sroczynska, P., Cruickshank, V.A., Bukowski, J.P., Miyagi, S., Bagger, F.O., Walfridsson, J., Schuster, M.B., Porse, B., Helin, K., shRNA screening identifies JMJD1C as being required for leukemia maintenance. Blood 123 (2014), 1870–1882.
53. 53 Chen, M., Zhu, N., Liu, X., Laurent, B., Tang, Z., Eng, R., Shi, Y., Armstrong, S.A., Roeder, R.G., JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors. Genes Dev. 29 (2015), 2123–2139.
54. 54 Ge, Y., LaFiura, K.M., Dombkowski, A.A., Chen, Q., Payton, S.G., Buck, S.A., Salagrama, S., Diakiw, A.E., Matherly, L.H., Taub, J.W., The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia 22 (2008), 521–529.
55. 55 Yáñez, A., Ng, M.Y., Hassanzadeh-Kiabi, N., Goodridge, H.S., IRF8 acts in lineage-committed rather than oligopotent progenitors to control neutrophil vs monocyte production. Blood 125 (2015), 1452–1459.
56. 56 Holtschke, T., Löhler, J., Kanno, Y., Fehr, T., Giese, N., Rosenbauer, F., Lou, J., Knobeloch, K.P., Gabriele, L., Waring, J.F., et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87 (1996), 307–317.
57. 57 Fotiadis, D., Kanai, Y., Palacín, M., The SLC3 and SLC7 families of amino acid transporters. Mol. Aspects Med. 34 (2013), 139–158.
58. 58 Yamanaka, R., Barlow, C., Lekstrom-Himes, J., Castilla, L.H., Liu, P.P., Eckhaus, M., Decker, T., Wynshaw-Boris, A., Xanthopoulos, K.G., Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice. Proc. Natl. Acad. Sci. USA 94 (1997), 13187–13192.
59. 59 Halene, S., Gaines, P., Sun, H., Zibello, T., Lin, S., Khanna-Gupta, A., Williams, S.C., Perkins, A., Krause, D., Berliner, N., C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx. Exp. Hematol. 38 (2010), 90–103.
60. 60 Francis, O.L., Payne, J.L., Su, R.J., Payne, K.J., Regulator of myeloid differentiation and function: The secret life of Ikaros. World J. Biol. Chem. 2 (2011), 119–125.
61. 61 Domen, J., Cheshier, S.H., Weissman, I.L., The role of apoptosis in the regulation of hematopoietic stem cells: Overexpression of Bcl-2 increases both their number and repopulation potential. J. Exp. Med. 191 (2000), 253–264.
62. 62 Elmore, S., Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35 (2007), 495–516.
63. 63 Yoon, K.W., Byun, S., Kwon, E., Hwang, S.Y., Chu, K., Hiraki, M., Jo, S.H., Weins, A., Hakroush, S., Cebulla, A., et al. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science, 349, 2015, 1261669.
64. 64 Wang, L., Le Mercier, I., Putra, J., Chen, W., Liu, J., Schenk, A.D., Nowak, E.C., Suriawinata, A.A., Li, J., Noelle, R.J., Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity. Proc. Natl. Acad. Sci. USA 111 (2014), 14846–14851.
65. 65 De Togni, P., Goellner, J., Ruddle, N.H., Streeter, P.R., Fick, A., Mariathasan, S., Smith, S.C., Carlson, R., Shornick, L.P., Strauss-Schoenberger, J., et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264 (1994), 703–707.
66. 66 Chiquet-Ehrismann, R., Tucker, R.P., Tenascins and the importance of adhesion modulation. Cold Spring Harb. Perspect. Biol., 3, 2011, 3.
67. 67 Yoshida, H., Okada, T., Haze, K., Yanagi, H., Yura, T., Negishi, M., Mori, K., Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6alpha and 6beta that activates the mammalian unfolded protein response. Mol. Cell. Biol. 21 (2001), 1239–1248.
68. 68 Yamamoto, M., Ma, J.S., Mueller, C., Kamiyama, N., Saiga, H., Kubo, E., Kimura, T., Okamoto, T., Okuyama, M., Kayama, H., et al. ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18. J. Exp. Med. 208 (2011), 1533–1546.
69. 69 Conduit, P.T., Wainman, A., Raff, J.W., Centrosome function and assembly in animal cells. Nat. Rev. Mol. Cell Biol. 16 (2015), 611–624.
70. 70 Zhang, Q., Zhu, H., Xu, X., Li, L., Tan, H., Cai, X., Inactivated Sendai virus induces apoptosis and autophagy via the PI3K/Akt/mTOR/p70S6K pathway in human non-small cell lung cancer cells. Biochem. Biophys. Res. Commun. 465 (2015), 64–70.
71. 71 Utsugi, M., Dobashi, K., Ono, A., Ishizuka, T., Matsuzaki, S., Hisada, T., Shimizu, Y., Kawata, T., Aoki, H., Kamide, Y., Mori, M., PI3K p110beta positively regulates lipopolysaccharide-induced IL-12 production in human macrophages and dendritic cells and JNK1 plays a novel role. J. Immunol. 182 (2009), 5225–5231.
72. 72 Dehghan, A., Dupuis, J., Barbalic, M., Bis, J.C., Eiriksdottir, G., Lu, C., Pellikka, N., Wallaschofski, H., Kettunen, J., Henneman, P., et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123 (2011), 731–738.
73. 73 Westra, H.J., Peters, M.J., Esko, T., Yaghootkar, H., Schurmann, C., Kettunen, J., Christiansen, M.W., Fairfax, B.P., Schramm, K., Powell, J.E., et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45 (2013), 1238–1243.
74. 74 Yanaba, K., Bouaziz, J.D., Matsushita, T., Magro, C.M., St Clair, E.W., Tedder, T.F., B-lymphocyte contributions to human autoimmune disease. Immunol. Rev. 223 (2008), 284–299.
75. 75 Orrù, V., Steri, M., Sole, G., Sidore, C., Virdis, F., Dei, M., Lai, S., Zoledziewska, M., Busonero, F., Mulas, A., et al. Genetic variants regulating immune cell levels in health and disease. Cell 155 (2013), 242–256.
76. 76 Sancho, D., Gómez, M., Viedma, F., Esplugues, E., Gordón-Alonso, M., García-López, M.A., de la Fuente, H., Martínez-A, C., Lauzurica, P., Sánchez-Madrid, F., CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis. J. Clin. Invest. 112 (2003), 872–882.
77. 77 Hu, X., Kim, H., Stahl, E., Plenge, R., Daly, M., Raychaudhuri, S., Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89 (2011), 496–506.
78. 78 Raj, T., Rothamel, K., Mostafavi, S., Ye, C., Lee, M.N., Replogle, J.M., Feng, T., Lee, M., Asinovski, N., Frohlich, I., et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344 (2014), 519–523.
79. 79 Malik, M., Simpson, J.F., Parikh, I., Wilfred, B.R., Fardo, D.W., Nelson, P.T., Estus, S., CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing. J. Neurosci. 33 (2013), 13320–13325.
80. 80 Ramasamy, A., Trabzuni, D., Guelfi, S., Varghese, V., Smith, C., Walker, R., De, T., Coin, L., de Silva, R., Cookson, M.R., et al. UK Brain Expression Consortium, North American Brain Expression Consortium. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat. Neurosci. 17 (2014), 1418–1428.
81. 81 Hambleton, S., Salem, S., Bustamante, J., Bigley, V., Boisson-Dupuis, S., Azevedo, J., Fortin, A., Haniffa, M., Ceron-Gutierrez, L., Bacon, C.M., et al. IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 365 (2011), 127–138.
82. 82 Hancock, A.M., Witonsky, D.B., Alkorta-Aranburu, G., Beall, C.M., Gebremedhin, A., Sukernik, R., Utermann, G., Pritchard, J.K., Coop, G., Di Rienzo, A., Adaptations to climate-mediated selective pressures in humans. PLoS Genet., 7, 2011, e1001375.
83. 83 Cserti, C.M., Dzik, W.H., The ABO blood group system and Plasmodium falciparum malaria. Blood 110 (2007), 2250–2258.
84. 84 Rijneveld, A.W., Levi, M., Florquin, S., Speelman, P., Carmeliet, P., van Der Poll, T., Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J. Immunol. 168 (2002), 3507–3511.
85. 85 Wilson, N.K., Foster, S.D., Wang, X., Knezevic, K., Schütte, J., Kaimakis, P., Chilarska, P.M., Kinston, S., Ouwehand, W.H., Dzierzak, E., et al. Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell 7 (2010), 532–544.
86. 86 Dowell, J.A., Korth-Bradley, J., Liu, H., King, S.P., Berger, M.S., Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse. J. Clin. Pharmacol. 41 (2001), 1206–1214.
87. 87 de Paulis, A., Montuori, N., Prevete, N., Fiorentino, I., Rossi, F.W., Visconte, V., Rossi, G., Marone, G., Ragno, P., Urokinase induces basophil chemotaxis through a urokinase receptor epitope that is an endogenous ligand for formyl peptide receptor-like 1 and -like 2. J. Immunol. 173 (2004), 5739–5748.
88. 88 Selleri, C., Montuori, N., Ricci, P., Visconte, V., Carriero, M.V., Sidenius, N., Serio, B., Blasi, F., Rotoli, B., Rossi, G., Ragno, P., Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 105 (2005), 2198–2205.
89. 89 Kwok, B., Hall, J.M., Witte, J.S., Xu, Y., Reddy, P., Lin, K., Flamholz, R., Dabbas, B., Yung, A., Al-Hafidh, J., et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 126 (2015), 2355–2361.
90. 90 Cargo, C.A., Rowbotham, N., Evans, P.A., Barrans, S.L., Bowen, D.T., Crouch, S., Jack, A.S., Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood 126 (2015), 2362–2365.
91. 91 Abdel-Wahab, O., Gao, J., Adli, M., Dey, A., Trimarchi, T., Chung, Y.R., Kuscu, C., Hricik, T., Ndiaye-Lobry, D., Lafave, L.M., et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J. Exp. Med. 210 (2013), 2641–2659.
92. 92 Dupuis, A., Gaub, M.P., Legrain, M., Drenou, B., Mauvieux, L., Lutz, P., Herbrecht, R., Chan, S., Kastner, P., Biclonal and biallelic deletions occur in 20% of B-ALL cases with IKZF1 mutations. Leukemia 27 (2013), 503–507.
93. 93 Mullighan, C.G., Miller, C.B., Radtke, I., Phillips, L.A., Dalton, J., Ma, J., White, D., Hughes, T.P., Le Beau, M.M., Pui, C.H., et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453 (2008), 110–114.
94. 94 Ouyang, W., Kolls, J.K., Zheng, Y., The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28 (2008), 454–467.
95. 95 Pistis, G., Okonkwo, S.U., Traglia, M., Sala, C., Shin, S.Y., Masciullo, C., Buetti, I., Massacane, R., Mangino, M., Thein, S.L., et al., CHARGE Consortium Hematology Working. Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans. PLoS ONE, 8, 2013, e69206.
96. 96 Migliorini, G., Fiege, B., Hosking, F.J., Ma, Y., Kumar, R., Sherborne, A.L., da Silva Filho, M.I., Vijayakrishnan, J., Koehler, R., Thomsen, H., et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood 122 (2013), 3298–3307.