Multiple Loci Are Associated with White Blood Cell Phenotypes

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White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

Vyšlo v časopise: Multiple Loci Are Associated with White Blood Cell Phenotypes. PLoS Genet 7(6): e32767. doi:10.1371/journal.pgen.1002113
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002113

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1. DaneshJCollinsRApplebyPPetoR 1998 Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 279 1477 1482

2. MadjidMAwanIWillersonJTCasscellsSW 2004 Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol 44 1945 1956

3. ShankarAWangJJRochtchinaEYuMCKeffordR 2006 Association between circulating white blood cell count and cancer mortality: a population-based cohort study. Arch Intern Med 166 188 194

4. RuggieroCMetterEJCherubiniAMaggioMSenR 2007 White blood cell count and mortality in the Baltimore Longitudinal Study of Aging. J Am Coll Cardiol 49 1841 1850

5. Lloyd-JonesDMCamargoCAAllenLAGiuglianoRPO'DonnellCJ 2003 Predictors of long-term mortality after hospitalization for primary unstable angina pectoris and non-ST-elevation myocardial infarction. Am J Cardiol 92 1155 1159

6. LeeCDFolsomARNietoFJChamblessLEShaharE 2001 White blood cell count and incidence of coronary heart disease and ischemic stroke and mortality from cardiovascular disease in African-American and White men and women: atherosclerosis risk in communities study. Am J Epidemiol 154 758 764

7. GrimmRHJrNeatonJDLudwigW 1985 Prognostic importance of the white blood cell count for coronary, cancer, and all-cause mortality. JAMA 254 1932 1937

8. GillumRFMussolinoMEMadansJH 2005 Counts of neutrophils, lymphocytes, and monocytes, cause-specific mortality and coronary heart disease: the NHANES-I epidemiologic follow-up study. Ann Epidemiol 15 266 271

9. FriedmanGDKlatskyALSiegelaubAB 1974 The leukocyte count as a predictor of myocardial infarction. N Engl J Med 290 1275 1278

10. BrownDWGilesWHCroftJB 2001 White blood cell count: an independent predictor of coronary heart disease mortality among a national cohort. J Clin Epidemiol 54 316 322

11. WheelerJGMussolinoMEGillumRFDaneshJ 2004 Associations between differential leucocyte count and incident coronary heart disease: 1764 incident cases from seven prospective studies of 30,374 individuals. Eur Heart J 25 1287 1292

12. RanaJSBoekholdtSMRidkerPMJukemaJWLubenR 2007 Differential leucocyte count and the risk of future coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population Study. J Intern Med 262 678 689

13. NietoFJSzkloMFolsomARRockRMercuriM 1992 Leukocyte count correlates in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 136 525 537

14. PiliaGChenWMScuteriAOrruMAlbaiG 2006 Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2 e132 doi:10.1371/journal.pgen.0020132

15. ReichDNallsMAKaoWHAkylbekovaELTandonA 2009 Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet 5 e1000360 doi:10.1371/journal.pgen.1000360

16. NallsMAWilsonJGPattersonNJTandonAZmudaJM 2008 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 81 87

17. GaneshSKZakaiNAvan RooijFJSoranzoNSmithAV 2009 Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 41 1191 1198

18. SoranzoNSpectorTDManginoMKuhnelBRendonA 2009 A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41 1182 1190

19. GudbjartssonDFBjornsdottirUSHalapiEHelgadottirASulemP 2009 Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41 342 347

20. KamataniYMatsudaKOkadaYKuboMHosonoN Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 42 210 215

21. PsatyBMO'DonnellCJGudnasonVLunettaKLFolsomAR 2009 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ Cardiovasc Genet 2 73 80

22. RaychaudhuriSPlengeRMRossinEJNgACPurcellSM 2009 Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet 5 e1000534 doi:10.1371/journal.pgen.1000534

23. VoightBFKudaravalliSWenXPritchardJK 2006 A map of recent positive selection in the human genome. PLoS Biol 4 e72 doi:10.1371/journal.pbio.0040072

24. HindorffLASethupathyPJunkinsHARamosEMMehtaJP 2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106 9362 9367

25. KamataniYMatsudaKOkadaYKuboMHosonoN 2010 Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 42 210 215

26. FerreiraMAHottengaJJWarringtonNMMedlandSEWillemsenG 2009 Sequence variants in three loci influence monocyte counts and erythrocyte volume. Am J Hum Genet 85 745 749

27. OkadaYKamataniYTakahashiAMatsudaKHosonoN 2010 Common variations in PSMD3-CSF3 and PLCB4 are associated with neutrophil count. Hum Mol Genet 19 2079 2085

28. 2009 Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 41 824 828

29. BeatyTHMurrayJCMarazitaMLMungerRGRuczinskiI A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet 42 525 529

30. BirnbaumSLudwigKUReutterHHermsSSteffensM 2009 Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet 41 473 477

31. Crowther-SwanepoelDBroderickPDi BernardoMCDobbinsSETorresM Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet 42 132 136

32. CuiROkadaYJangSGKuJLParkJG Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population. Gut

33. DuboisPCTrynkaGFrankeLHuntKARomanosJ Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42 295 302

34. EastonDFPooleyKADunningAMPharoahPDThompsonD 2007 Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 1087 1093

35. EelesRAKote-JaraiZAl OlamaAAGilesGGGuyM 2009 Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet 41 1116 1121

36. EelesRAKote-JaraiZGilesGGOlamaAAGuyM 2008 Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40 316 321

37. Enciso-MoraVBroderickPMaYJarrettRFHjalgrimH A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 42 1126 1130

38. FerreiraRCPan-HammarstromQGrahamRRGatevaVFontanG Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nat Genet 42 777 780

39. FletcherOJohnsonNOrrNHoskingFJGibsonLJ Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 103 425 435

40. FrankeAMcGovernDPBarrettJCWangKRadford-SmithGL Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42 1118 1125

41. GoodeELChenevix-TrenchGSongHRamusSJNotaridouM A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42 874 879

42. GrantSFWangKZhangHGlabersonWAnnaiahK 2009 A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr 155 909 913

43. GudmundssonJSulemPGudbjartssonDFBlondalTGylfasonA 2009 Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat Genet 41 1122 1126

44. GudmundssonJSulemPManolescuAAmundadottirLTGudbjartssonD 2007 Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39 631 637

45. HansonRLCraigDWMillisMPYeattsKAKobesS 2007 Identification of PVT1 as a candidate gene for end-stage renal disease in type 2 diabetes using a pooling-based genome-wide single nucleotide polymorphism association study. Diabetes 56 975 983

46. KiemeneyLASulemPBesenbacherSVermeulenSHSigurdssonA A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet 42 415 419

47. KiemeneyLAThorlaciusSSulemPGellerFAbenKK 2008 Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet 40 1307 1312

48. Lango AllenHEstradaKLettreGBerndtSIWeedonMN Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467 832 838

49. MelzerDPerryJRHernandezDCorsiAMStevensK 2008 A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4 e1000072 doi:10.1371/journal.pgen.1000072

50. RothmanNGarcia-ClosasMChatterjeeNMalatsNWuX A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet 42 978 984

51. SheteSHoskingFJRobertsonLBDobbinsSESansonM 2009 Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 41 899 904

52. TakataRAkamatsuSKuboMTakahashiAHosonoN Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat Genet 42 751 754

53. TenesaAFarringtonSMPrendergastJGPorteousMEWalkerM 2008 Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40 631 637

54. ThomasGJacobsKBYeagerMKraftPWacholderS 2008 Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40 310 315

55. TomlinsonIWebbECarvajal-CarmonaLBroderickPKempZ 2007 A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39 984 988

56. TomlinsonIPWebbECarvajal-CarmonaLBroderickPHowarthK 2008 A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40 623 630

57. TurnbullCAhmedSMorrisonJPernetDRenwickA Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42 504 507

58. YeagerMOrrNHayesRBJacobsKBKraftP 2007 Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39 645 649

59. ZankeBWGreenwoodCMRangrejJKustraRTenesaA 2007 Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39 989 994

60. SimmonsPJMasinovskyBLongeneckerBMBerensonRTorok-StorbB 1992 Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells. Blood 80 388 395

61. AvecillaSTHattoriKHeissigBTejadaRLiaoF 2004 Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 10 64 71

62. MoffattMFKabeschMLiangLDixonALStrachanD 2007 Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448 470 473

63. O'MahonyDSPhamUIyerRHawnTRLilesWC 2008 Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages. Int J Med Sci 5 1 8

64. ValenteJFAlexanderJWLiBGNoelJGCusterDA 2002 Effect of in vivo infusion of granulocyte colony-stimulating factor on immune function. Shock 17 23 29

65. NagataSTsuchiyaMAsanoSKaziroYYamazakiT 1986 Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature 319 415 418

66. SaitoTUsuiNAsaiODobashiNYanoS 2007 Elevated serum levels of human matrix metalloproteinase-9 (MMP-9) during the induction of peripheral blood stem cell mobilization by granulocyte colony-stimulating factor (G-CSF). J Infect Chemother 13 426 428

67. SkibolaCFBracciPMHalperinECondeLCraigDW 2009 Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat Genet 41 873 875

68. FellayJGeDShiannaKVColomboSLedergerberB 2009 Common genetic variation and the control of HIV-1 in humans. PLoS Genet 5 e1000791 doi:10.1371/journal.pgen.1000791

69. ValdimarssonH 2007 The genetic basis of psoriasis. Clin Dermatol 25 563 567

70. CaponFBijlmakersMJWolfNQuarantaMHuffmeierU 2008 Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet 17 1938 1945

71. De JagerPLJiaXWangJde BakkerPIOttoboniL 2009 Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41 776 782

72. LimouSLe ClercSCoulongesCCarpentierWDinaC 2009 Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). J Infect Dis 199 419 426

73. LiuYHelmsCLiaoWZabaLCDuanS 2008 A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 4 e1000041 doi:10.1371/journal.pgen.1000041

74. NairRPDuffinKCHelmsCDingJStuartPE 2009 Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41 199 204

75. PelakKGoldsteinDBWalleyNMFellayJGeD 2010 Host determinants of HIV-1 control in African Americans. J Infect Dis 201 1141 1149

76. QuanCRenYQXiangLHSunLDXuAE 2010 Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet 42 614 618

77. TsaiFYOrkinSH 1997 Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood 89 3636 3643

78. LabbayeCValtieriMBarberiTMecciaEMasellaB 1995 Differential expression and functional role of GATA-2, NF-E2, and GATA-1 in normal adult hematopoiesis. J Clin Invest 95 2346 2358

79. O'RourkeFALaPlanteJMFeinsteinMB 2003 Antisense-mediated loss of calcium homoeostasis endoplasmic reticulum protein (CHERP; ERPROT213-21) impairs Ca2+ mobilization, nuclear factor of activated T-cells (NFAT) activation and cell proliferation in Jurkat T-lymphocytes. Biochem J 373 133 143

80. ChiuCTeboMInglesJYeatesLArthurJW 2007 Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 43 337 343

81. de BakkerPIFerreiraMAJiaXNealeBMRaychaudhuriS 2008 Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet 17 R122 128

82. WillerCJLiYAbecasisGR 2010 METAL: Fast and efficient meta-analysis of genomewide association scans. Bioinformatics

83. Barbosa-MoraisNLDunningMJSamarajiwaSADarotJFRitchieME 2010 A re-annotation pipeline for Illumina BeadArrays: improving the interpretation of gene expression data. Nucleic Acids Res 38 e17

84. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575