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Nature Research, Nature Genetics, 8(48), p. 867-876

DOI: 10.1038/ng.3607



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Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

Journal article published in 2016 by Nathan Pankratz, V. S. (Shane) Pankratz, Ursula M. (Ursula) Schick, Yi Zhou, Wei Zhou, Tarunveer Singh Ahluwalia ORCID, Maria Laura Allende, Paul L. Auer, Jette Bork-Jensen, Jennifer A. Brody, Ming-Huei Chen, Vinna Clavo, John D. (John D.) Eicher, Niels Grarup ORCID, Elliott J. (Elliott J.) Hagedorn and other authors.
This paper is available in a repository.
This paper is available in a repository.

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Data provided by SHERPA/RoMEO


Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.