title: Trans-ethnic meta-analysis of white blood cell phenotypes.
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.
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authors.affiliation: Department of Epidemiology Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, The Netherlands.
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authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA NHLBI Framingham Heart Study, Bethesda, MD, USA.
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authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
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authors.affiliation: GeneSTAR Research Program, Division of General Internal Medicine.
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authors.affiliation: GeneSTAR Research Program, Division of General Internal Medicine.
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authors.affiliation: GeneSTAR Research Program, Division of General Internal Medicine Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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authors.affiliation: Department of Epidemiology Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, The Netherlands.
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authors.affiliation: Department of Epidemiology Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, The Netherlands.
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authors.initials: CM
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authors.affiliation: Department of Epidemiology ErasmusAGE, Department of Epidemiology Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, The Netherlands.
authors.forename: Oscar H
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authors.affiliation: Laboratory of Genetics.
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authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: 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.
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authors.affiliation: 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.
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mesh_terms: D001741:Black or African American; D044466:Asian People; D001499:Bayes Theorem; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D015810:Linkage Disequilibrium; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D044465:White People
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