Trans-ethnic meta-analysis of white blood cell phenotypes.
Keller MF., Reiner AP., Okada Y., van Rooij FJ., Johnson AD., Chen MH., Smith AV., Morris AP., Tanaka T., Ferrucci L., Zonderman AB., Lettre G., Harris T., Garcia M., Bandinelli S., Qayyum R., Yanek LR., Becker DM., Becker LC., Kooperberg C., Keating B., Reis J., Tang H., Boerwinkle E., Kamatani Y., Matsuda K., Kamatani N., Nakamura Y., Kubo M., Liu S., Dehghan A., Felix JF., Hofman A., Uitterlinden AG., van Duijn CM., Franco OH., Longo DL., Singleton AB., Psaty BM., Evans MK., Cupples LA., Rotter JI., O'Donnell CJ., Takahashi A., Wilson JG., Ganesh SK., Nalls MA., CHARGE Hematology None., COGENT None., BioBank Japan Project (RIKEN) Working Groups None.
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.