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

Research output: Contribution to journalArticle

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

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Original languageEnglish
Pages (from-to)867-876
Number of pages10
JournalNature Genetics
Volume48
Issue number8
Early online date11 Jul 2016
DOIs
Publication statusPublished - 1 Aug 2016

Abstract

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.

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