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Hum Mol Genet. 2014 Dec 20;23(25):6944-60. doi: 10.1093/hmg/ddu401. Epub 2014 Aug 5.

Trans-ethnic meta-analysis of white blood cell phenotypes.

Collaborators (160)

Arepalli S, Bandinelli S, Biffi A, Bis JC, Boerwinkle E, Chakravarti A, Chen MH, Chong S, Coresh J, Couper DJ, Cupples L, Dehghan A, Do'ring A, Eiriksdottir G, Felix JF, Ferrucci L, Folsom AR, Fox CS, Frayling TM, Ganesh SK, Garcia M, Garner SF, Gasparini P, Gieger C, Glazer NL, Gouskova NA, Greinacher A, Gudnason V, Harris TB, Hernandez DG, Hofman A, Illig T, Kamatani Y, Kamatani N, Kubo M, Kuhnel B, Lagou V, Lettre G, Levi D, Lin J, Liu Y, Longo DL, Lumley T, Mangino M, Matsuda K, Meisinger C, Melzer D, Menzel S, Moore M, Nakamura Y, Nalls MA, Nauck M, O'Donnell CJ, Okada Y, Oostra BA, Ouwehand WH, Patel KV, Pirastu N, Pistis G, Prokisch H, Prokopenko I, Psaty BM, Reiner AP, Rendon A, Sambrook J, Singleton AB, Smith AV, Soranzo N, Spector TD, Stephens J, Stumvoll M, Takahashi A, Tanaka T, Tanaka T, Taylor K, Teumer A, Thein SL, To'njes A, Toniolo D, Tsunoda T, Uitterlinden AG, van Duijn CM, van Rooij FJ, Vo'lker U, Vo'lzke H, Wichmann H-, Wiggins KL, Wilson JG, Witteman JC, Wood AR, Yamamoto K, Yang Q, Zakai NA, Arepalli S, Austin MA, Becker DM, Britton A, Chen Z, Couper D, Curb J, Dean E, Eaton CB, Evans MK, Folsom AR, Fornage M, Ganesh SK, Grant SF, Harris TB, Hernandez D, Kamatini N, Keating BJ, Kubo M, LaCroix A, Lange LA, Lettre G, Liu S, Liu Y, Lohman K, Mathias R, Meng Y, Mohler ER 3rd, Musani S, Nakamura Y, Nalls MA, O'Donnell CJ, Okada Y, Palmer CD, Papanicolaou GJ, Patel KV, Reiner AP, Singleton AB, Snively BM, Takahashi A, Tang H, Taylor HA Jr, Taylor K, Thomson C, Wilson JG, Yanek LR, Yang L, Ziv E, Zonderman AB, Higasa K, Hirota T, Hosono N, Kamatani Y, Kamatani N, Kubo M, Kumasaka N, Matsuda K, Nakamura Y, Ohmiya H, Okada Y, Takahashi A, Tamari M, Tanaka T, Tanaka T, Tsunoda T, Yamaguchi-Kabata Y, Yamamoto K.

Author information

1
Laboratory of Neurogenetics Department of Biological Anthropology, Temple University, Philadelphia, PA, USA.
2
Department of Epidemiology Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
3
Laboratory for Statistical Analysis Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
4
Department of Epidemiology Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, The Netherlands.
5
Cardiovascular Epidemiology and Human Genomics Branch, NHLBI Division of Intramural Research, Bethesda, MD, USA NHLBI Framingham Heart Study, Bethesda, MD, USA.
6
Department of Neurology, Boston University School of Medicine, Boston, MA, USA NHLBI Framingham Heart Study, Bethesda, MD, USA.
7
Icelandic Heart Association, Kopavogur, Iceland University of Iceland, Reykjavik, Iceland.
8
Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Department of Biostatistics, University of Liverpool, Liverpool, UK.
9
Longitudinal Studies Section, Clinical Research Branch.
10
Behavioral Epidemiology Section, Laboratory of Epidemiology & Population Sciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
11
Montreal Heart Institute, Montréal, Canada Département de Médecine, Université de Montréal, Montréal, Canada.
12
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
13
Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
14
GeneSTAR Research Program, Division of General Internal Medicine.
15
GeneSTAR Research Program, Division of General Internal Medicine Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
16
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
17
Center for Applied Genomics, Children's Hospital of Philadelphia, PA, USA Department of Pediatrics, University of Pennsylvania, PA, USA.
18
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
19
Stanford University School of Medicine, Stanford, CA 94305, USA.
20
The Brown Foundation, Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas, Houston, TX, USA.
21
Laboratory for Statistical Analysis.
22
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
23
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Medicine Department of Surgery, Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA.
24
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
25
Department of Epidemiology Department of Medicine, Brown University, Providence, RI, USA.
26
Department of Epidemiology Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, The Netherlands.
27
Department of Epidemiology ErasmusAGE, Department of Epidemiology Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, The Netherlands.
28
Laboratory of Genetics.
29
Laboratory of Neurogenetics.
30
Cardiovascular Health Research Unit Department of Medicine Department of Epidemiology and Health Services, University of Washington, Seattle, WA, USA Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
31
Health Disparities Research Section, Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
32
NHLBI Framingham Heart Study, Bethesda, MD, USA Boston University Department of Statistics, Boston, MA, USA.
33
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
34
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
35
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA sganesh@med.umich.edu nallsm@mail.nih.gov.
36
Laboratory of Neurogenetics sganesh@med.umich.edu nallsm@mail.nih.gov.

Abstract

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

PMID:
25096241
PMCID:
PMC4245044
DOI:
10.1093/hmg/ddu401
[Indexed for MEDLINE]
Free PMC Article

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