Dataset Information

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.

SUBMITTER: Keller MF

PROVIDER: S-EPMC4245044 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Keller Margaux F MF Reiner Alexander P AP Okada Yukinori Y van Rooij Frank J A FJ Johnson Andrew D AD Chen Ming-Huei MH Smith Albert V AV Morris Andrew P AP Tanaka Toshiko T Ferrucci Luigi L Zonderman Alan B AB Lettre Guillaume G Harris Tamara T Garcia Melissa M Bandinelli Stefania S Qayyum Rehan R Yanek Lisa R LR Becker Diane M DM Becker Lewis C LC Kooperberg Charles C Keating Brendan B Reis Jared J Tang Hua H Boerwinkle Eric E Kamatani Yoichiro Y Matsuda Koichi K Kamatani Naoyuki N Nakamura Yusuke Y Kubo Michiaki M Liu Simin S Dehghan Abbas A Felix Janine F JF Hofman Albert A Uitterlinden André G AG van Duijn Cornelia M CM Franco Oscar H OH Longo Dan L DL Singleton Andrew B AB Psaty Bruce M BM Evans Michelle K MK Cupples L Adrienne LA Rotter Jerome I JI O'Donnell Christopher J CJ Takahashi Atsushi A Wilson James G JG Ganesh Santhi K SK Nalls Mike A MA

Human molecular genetics 20140805 25

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 ...[more]

PMID: 25096241

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Project description:Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: β = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (β = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (β = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

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

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

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