Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits
Creators: name: Lehtimaki, Terho
name: Grarup, Niels
name: Hofman, Albert
name: Launer, Lenore J.
name: Liewald, David C.
name: Smith, Albert Vernon
name: Yang, Min-Lee
name: Di Sant, Amanda M. Rosa
name: Taylor, Kent D.
name: Pedersen, Oluf
name: O'Donnell, Christopher J.
name: Tracy, Russell P.
name: Hansen, Torben
name: Franceschini, Nora
name: Jia, Jia
name: Bork-Jensen, Jette
name: Johnson, Andrew D.
name: Zon, Leonard I.
name: Floyd, James S.
name: Bottinger, Erwin P.
name: Harris, Tamara B.
name: Loos, Ruth J. F.
name: Marioni, Riccardo E.
name: Proia, Richard L.
name: Clavo, Vinna
name: Deary, Ian J.
name: Reiner, Alex P.
name: Jackson, Rebecca D.
name: Brody, Jennifer A.
name: Ahluwalia, Tarunveer Singh
name: Starr, John M.
name: Pankratz, Nathan
name: Allende, Maria Laura
name: Pazoki, Raha
name: Hunker, Kristina
name: Garcia, Melissa E.
name: Hagedorn, Elliott J.
name: Lu, Yingchang
name: Zhou, Yi
name: Wilson, James G.
name: Ganesh, Santhi K.
name: Raitakari, Olli T.
name: Cushman, Mary
name: Rotter, Jerome I.
name: Lyytikainen, Leo-Pekka
name: Schick, Ursula M.
name: Zhang, Xiaoling
name: Gudnason, Vilmundur
name: Linneberg, Allan
name: Numans, Mattijs E.
name: De Bakker, Paul I. W.
name: Huo, Yong
name: Dong, Liguang
name: Zhou, Wei
name: Thuesen, Betina Heinsbek
name: Asselbergs, Folkert W.
name: Dehghan, Abbas
name: Van Rooij, Frank J.A.
name: Kahonen, Mika
name: Liu, Yongmei
name: Boerwinkle, Eric
name: Franco, Oscar H.
name: Nalls, Mike A.
name: Chen, Ming-Huei
name: Manichaikul, Ani
name: Nguyen, Vy M.
name: Eicher, John D.
name: Hu, Bella
name: Wang, Jiansong
name: Rivadeneira, Fernando
name: Rich, Stephen S.
name: Uitterlinden, Andre G.
name: Wang, Judy
name: Grove, Megan L.
name: Psaty, Bruce M.
name: Adrienne Cupples, 
name: Feitosa, Mary F.
name: Borecki, Ingrid B.
name: Leusink, Maarten
name: Auer, Paul L.
name: Zhang, Yan
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2016

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