TY - JOUR
T1 - Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits
AU - Pankratz, Nathan
AU - Schick, Ursula M
AU - Zhou, Yi
AU - Zhou, Wei-Wei
AU - Ahluwalia, Tarun Veer Singh
AU - Allende, Maria Laura
AU - Auer, Paul L
AU - Bork-Jensen, Jette
AU - Brody, Jennifer A
AU - Chen, Ming-Huei
AU - Clavo, Vinna
AU - Eicher, John D
AU - Grarup, Niels
AU - Hagedorn, Elliott J.
AU - Hu, Bella
AU - Hunker, Kristina
AU - Johnson, Andrew D
AU - Leusink, Maarten
AU - Lu, Yingchang
AU - Lyytikainen, Leo-Pekka
AU - Manichaikul, Ani
AU - Marioni, Riccardo E
AU - Nalls, Mike A
AU - Pazoki, Raha
AU - Smith, Albert Vernon
AU - van Rooij, Frank J A
AU - Yang, Min-Lee
AU - Zhang, Xiaoling
AU - Zhang, Yan
AU - Asselbergs, Folkert W
AU - Boerwinkle, Eric
AU - Borecki, Ingrid B
AU - Bottinger, Erwin P
AU - Cushman, Mary
AU - de Bakker, Paul I W
AU - Deary, Ian J
AU - Dong, Liguang
AU - Feitosa, Mary F
AU - Floyd, James S
AU - Franceschini, Nora
AU - Franco, Oscar H
AU - Garcia, Melissa E
AU - Grove, Megan L
AU - Gudnason, Vilmundur
AU - Hansen, Torben
AU - Harris, Tamara B
AU - Hofman, Albert
AU - Jackson, Rebecca D
AU - Linneberg, Allan
AU - Pedersen, Oluf
AU - CHARGE Consortium Hematology Working Group
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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.
U2 - 10.1038/ng.3607
DO - 10.1038/ng.3607
M3 - Journal article
C2 - 27399967
VL - 48
SP - 867
EP - 876
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 8
ER -