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

被引：36

作者：

Pankratz, Nathan ^{[1
]}

Schick, Ursula M. ^{[2
,3
]}

Zhou, Yi ^{[4
]}

Zhou, Wei ^{[5
]}

Ahluwalia, Tarunveer Singh ^{[6
,7
]}

Allende, Maria Laura ^{[8
]}

Auer, Paul L. ^{[9
]}

Bork-Jensen, Jette ^{[6
]}

Brody, Jennifer A. ^{[10
]}

Chen, Ming-Huei ^{[11
,12
]}

Clavo, Vinna ^{[13
,14
]}

Eicher, John D. ^{[12
,15
]}

Grarup, Niels ^{[6
]}

Hagedorn, Elliott J. ^{[4
]}

Hu, Bella ^{[4
]}

Hunker, Kristina ^{[13
,14
]}

Johnson, Andrew D. ^{[12
,15
]}

Leusink, Maarten ^{[16
]}

Lu, Yingchang ^{[2
,17
]}

Lyytikainen, Leo-Pekka ^{[18
,19
]}

Manichaikul, Ani ^{[20
]}

Marioni, Riccardo E. ^{[21
,22
,23
]}

Nalls, Mike A. ^{[24
]}

Pazoki, Raha ^{[25
]}

Smith, Albert Vernon ^{[26
,27
]}

van Rooij, Frank J. A. ^{[25
]}

Yang, Min-Lee ^{[13
,14
]}

Zhang, Xiaoling ^{[12
,28
]}

Zhang, Yan ^{[29
]}

Asselbergs, Folkert W. ^{[30
,31
,32
]}

Boerwinkle, Eric ^{[33
,34
]}

Borecki, Ingrid B. ^{[35
]}

Bottinger, Erwin P. ^{[2
]}

Cushman, Mary ^{[36
]}

de Bakker, Paul I. W. ^{[37
,38
]}

Deary, Ian J. ^{[21
,39
]}

Dong, Liguang ^{[40
]}

Feitosa, Mary F. ^{[35
]}

Floyd, James S. ^{[10
]}

Franceschini, Nora ^{[41
]}

Franco, Oscar H. ^{[25
]}

Garcia, Melissa E. ^{[42
]}

Grove, Megan L. ^{[33
]}

Gudnason, Vilmundur ^{[26
,27
]}

Hansen, Torben ^{[6
]}

Harris, Tamara B. ^{[42
]}

Hofman, Albert ^{[25
,43
]}

Jackson, Rebecca D. ^{[44
]}

Jia, Jia ^{[29
]}

Kahonen, Mika ^{[45
,46
]}

机构：

[1] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[2] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA

[3] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[4] Harvard Univ, Stem Cell & Regenerat Biol Dept, Cambridge, MA 02138 USA

[5] Univ Michigan, Dept Computat Med & Biostat, Ann Arbor, MI 48109 USA

[6] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[7] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[8] NIDDKD, Genet Dev & Dis Branch, US Natl Inst Hlth, Bethesda, MD USA

[9] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA

[10] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[11] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[12] NHLBI, Framingham Heart Study, Framingham, MA USA

[13] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[14] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[15] NHLBI, Populat Sci Branch, Intramural Res Program, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA

[16] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands

[17] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

[18] Fimlab Labs, Dept Clin Chem, Tampere, Finland

[19] Univ Tampere, Sch Med, Tampere, Finland

[20] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[21] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[22] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland

[23] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[24] NIA, Neurogenet Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA

[25] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[26] Iceland Heart Assoc, Kopavogur, Iceland

[27] Univ Iceland, Fac Med, Kopavogur, Iceland

[28] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[29] Peking Univ, Hosp 1, Dept Cardiol, Beijing 100871, Peoples R China

[30] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[31] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands

[32] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England

[33] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA

[34] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[35] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[36] Univ Vermont, Dept Med, Div Hematol Oncol, Burlington, VT USA

[37] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands

[38] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands

[39] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[40] Peking Univ, Shougang Hosp, Jin Ding St Community Hlth Ctr, Beijing, Peoples R China

[41] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA

[42] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, US Natl Inst Hlth, Bethesda, MD 20892 USA

[43] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[44] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA

[45] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland

[46] Univ Tampere, Sch Med, Tampere, Finland

[47] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark

[48] Rigshosp, Dept Clin Expt Res, Glostrup, Denmark

[49] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark

[50] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 08期

基金：

美国国家卫生研究院; 英国生物技术与生命科学研究理事会; 芬兰科学院;

关键词：

GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SUSCEPTIBILITY LOCI; LYMPHOCYTE EGRESS; CROHNS-DISEASE; FUNCTIONAL PREDICTIONS; CHARGE CONSORTIUM; KIDNEY-FUNCTION; LARGE-SCALE; DIFFERENTIATION;

D O I：

10.1038/ng.3607

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：867 / +

页数：12

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