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

TitleMeta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits.
Publication TypeJournal Article
Year of Publication2016
Corporate AuthorsCHARGE Consortium Hematology Working Group
JournalNat Genet
Volume48
Issue8
Pagination867-76
Date Published2016 08
ISSN1546-1718
KeywordsAnimals, Erythrocyte Count, Erythrocytes, Ethnic Groups, Exome, Female, Genetic Loci, Genome-Wide Association Study, Hematocrit, Humans, Male, Mice, Quantitative Trait Loci, Receptors, Lysosphingolipid, Zebrafish
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.

DOI10.1038/ng.3607
Alternate JournalNat Genet
PubMed ID27399967
PubMed Central IDPMC5145000
Grant ListRC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
R24 OD017870 / OD / NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL122684 / HL / NHLBI NIH HHS / United States
R25 CA094880 / CA / NCI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 AG032098 / AG / NIA NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HL048801 / HL / NHLBI NIH HHS / United States
U54 DK110805 / DK / NIDDK NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
R01 HL088215 / HL / NHLBI NIH HHS / United States
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 HL117078 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
U01 HG005152 / HG / NHGRI NIH HHS / United States
R01 HL087700 / HL / NHLBI NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
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HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
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UL1 RR024156 / RR / NCRR NIH HHS / United States
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RC2 HL102924 / HL / NHLBI NIH HHS / United States
U01 CA137088 / CA / NCI NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States