Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits.

[1]  Christian Gieger,et al.  Multiple Loci Are Associated with White Blood Cell Phenotypes , 2011, PLoS genetics.

[2]  Yusuke Nakamura,et al.  Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus. , 2011, Human molecular genetics.

[3]  R. Puntoni,et al.  Cross-sectional study of biomarkers of exposure and biological effect on monozygotic twins discordant for smoking , 2011, Clinical chemistry and laboratory medicine.

[4]  H. Hakonarson,et al.  Analysing biological pathways in genome-wide association studies , 2010, Nature Reviews Genetics.

[5]  Silvano Sozzani,et al.  Nomenclature of monocytes and dendritic cells in blood. , 2010, Blood.

[6]  P. Visscher,et al.  Common SNPs explain a large proportion of heritability for human height , 2011 .

[7]  Jing Cui,et al.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci , 2010, Nature Genetics.

[8]  Y. Kamatani,et al.  A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. , 2010, Human Molecular Genetics.

[9]  Y. Kamatani,et al.  Common variations in PSMD3-CSF3 and PLCB4 are associated with neutrophil count. , 2010, Human molecular genetics.

[10]  Yusuke Nakamura,et al.  Genome-wide association study of hematological and biochemical traits in a Japanese population , 2010, Nature Genetics.

[11]  Nicole Soranzo,et al.  Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. , 2010, American journal of human genetics.

[12]  M. Rubin,et al.  Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort , 2009, Modern Pathology.

[13]  Sarah E Medland,et al.  Sequence variants in three loci influence monocyte counts and erythrocyte volume. , 2009, American journal of human genetics.

[14]  Christian Gieger,et al.  A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium , 2009, Nature Genetics.

[15]  Gonçalo Abecasis,et al.  Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels , 2009, Nature Genetics.

[16]  Ian H. Frazer,et al.  Common variants in TMPRSS6 are associated with iron status and erythrocyte volume , 2009, Nature Genetics.

[17]  Christian Gieger,et al.  Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium , 2009, Nature Genetics.

[18]  J. Denburg,et al.  Haemopoietic processes in allergic disease: eosinophil/basophil development , 2009, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[19]  M. Lathrop,et al.  The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells. , 2009, Blood.

[20]  M. Gerstein,et al.  N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer. , 2009, Neoplasia.

[21]  J. Fahy,et al.  Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. , 2009, Proceedings of the American Thoracic Society.

[22]  Simon C. Potter,et al.  A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. , 2009, Blood.

[23]  D. Postma,et al.  Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction , 2009, Nature Genetics.

[24]  K. Lunetta,et al.  Methods in Genetics and Clinical Interpretation Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts , 2010 .

[25]  R. Locksley,et al.  Basophils: a nonredundant contributor to host immunity. , 2009, Immunity.

[26]  Christian Gieger,et al.  A genome-wide association study identifies three loci associated with mean platelet volume. , 2009, American journal of human genetics.

[27]  K. Akashi,et al.  Origin of basophils and mast cells. , 2009, Allergology international : official journal of the Japanese Society of Allergology.

[28]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[29]  Andrew D. Johnson,et al.  SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap , 2008, Bioinform..

[30]  Yusuke Nakamura,et al.  Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. , 2008, American journal of human genetics.

[31]  Elizabeth A. Kruse,et al.  The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells , 2008, Nature Immunology.

[32]  Richa Saxena,et al.  A common variant of HMGA2 is associated with adult and childhood height in the general population , 2007, Nature Genetics.

[33]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[34]  K. Sumiyama,et al.  Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. , 2007, Genomics.

[35]  Pardis C Sabeti,et al.  A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC , 2006, Nature Genetics.

[36]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[37]  Lisa A. Lambert,et al.  Molecular Evolution of the Transferrin Receptor/Glutamate Carboxypeptidase II Family , 2006, Journal of Molecular Evolution.

[38]  Yusuke Nakamura,et al.  [BioBank Japan project]. , 2005, Nihon rinsho. Japanese journal of clinical medicine.

[39]  M. W. Foster,et al.  Integrating ethics and science in the International HapMap Project , 2004, Nature Reviews Genetics.

[40]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[41]  B. Engelhardt,et al.  Alpha4 integrins as therapeutic targets in autoimmune disease. , 2003, The New England journal of medicine.

[42]  R. Scheller,et al.  Amisyn, a Novel Syntaxin-binding Protein That May Regulate SNARE Complex Assembly* , 2002, The Journal of Biological Chemistry.

[43]  TD Spector,et al.  Genetic influence on peripheral blood T lymphocyte levels , 2000, Genes and Immunity.

[44]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[45]  N. Martin,et al.  Genetic and environmental causes of variation in basal levels of blood cells , 1999, Twin Research.

[46]  L. Zon,et al.  Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription , 1993 .

[47]  L. Zon,et al.  Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription. , 1993, Blood.

[48]  R. Gully,et al.  Correlation of absolute basophil and eosinophil counts in blood from institutionalized human subjects. , 1956, Journal of applied physiology.