期刊
PLOS GENETICS
卷 7, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002113
关键词
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资金
- NIA/NIH [AG000932-02]
- NIH [N01-AG-12100, HHSN268200625226C, UL1RR025005, HHSN268200782096C, R01 AG24233-01, R01HL087641, R01HL59367, R01HL86694, U01HG004402]
- NIA [1R01AG032098-01A1]
- Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- National Heart, Lung, and Blood Institute [R01HL087641, R01HL59367, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- NIH Roadmap for Medical Research
- Boston University School of Medicine
- National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix for genotyping services [N02-HL-6-4278]
- NIH, National Institute on Aging, NIA [N01AG62101, N01AG62103, N01AG62106]
- Italian Ministry of Health [ICS 110.1RS97.71]
- U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336]
- National Institute on Aging, National Institutes of Health, USA
- National Heart, Lung and Blood Institute [HL085251, HL087652, R01 HL-071862]
- Health Ministry project [RF-FSR-2007-647201]
- Fondazione Compagnia di San Paolo
- Fondazione Cassa di Risparmio di Alessandria
- Helmholtz Zentrum Munchen
- German Research Center for Environmental Health, Neuherberg, Germany
- German Federal Ministry of Education and Research (BMBF)
- German National Genome Research Network (NGFN)
- Munich Center of Health Sciences (MC Health)
- LMUinnovativ
- Netherlands Organization of Scientific Research NWO [175.010.2005.011, 911.03.012, 918-76-619]
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative (NGI)/NWO [050 060 810]
- Erasmus Medical Center and Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Netherlands Heart Foundation
- Ministry of Education, Culture, and Science
- Ministry of Health, Welfare, and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Wellcome Trust [076113/C/04/Z, 091746/Z/10/Z]
- European Community [HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, QLG2-CT-2002-01254]
- Dept of Health via the National Institute for Health Research (NIHR)
- NIHR
- Biotechnology and Biological Sciences Research Council (BBSRC) [G20234]
- Juvenile Diabetes Research Foundation [WT061858]
- National Institute of Health Research of England
- German Center for Diabetes Research
- Systems Biology of Metabotypes [SysMBo #0315494A]
- German Research Council [KFO-152]
- IZKF [B27]
- German Diabetes Association
- European Community
- ENGAGE project [HEALTH-F4-2007-201413]
- NIH, National Institute on Aging
- National Center on Minority Health and Health Disparities [Z01-AG000513]
- National Heart, Lung, and Blood Institute (NHLBI) [U01 HL72518, R01 HL087698-01]
- NIH/National Institute of Nursing Research [R01 NR08153]
- NIH/National Center for Research Resources [M01-RR000052]
- Johns Hopkins General Clinical Research Center
- National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]
- Ministry of Education, Culture, Sports, Science, and Technology, Japan
- British Heart Foundation [RG/09/012/28096] Funding Source: researchfish
- Medical Research Council [G0000111, MC_U105260799] Funding Source: researchfish
- MRC [MC_U105260799, G0000111] Funding Source: UKRI
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.
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