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

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; Riccardo Marioni; 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; Ian Deary; 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; John Starr; 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

doi:10.1038/ng.3607

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

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 LyytikainenAni Manichaikul, Riccardo Marioni, 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, Ian Deary, 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, John Starr, 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	867-876
Number of pages	10
Journal	Nature Genetics
Volume	48
Issue number	8
Early online date	11 Jul 2016
DOIs	https://doi.org/10.1038/ng.3607
Publication status	Published - 1 Aug 2016

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10.1038/ng.3607

Marioni et al_Main_Text_NG-A40978R-3Accepted author manuscript, 266 KB

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Pankratz, N., Schick, U. M., Zhou, Y., Zhou, W., Ahluwalia, T. S., Allende, M. L., Auer, P. L., Bork-Jensen, J., Brody, J. A., Chen, M. H., Clavo, V., Eicher, J. D., Grarup, N., Hagedorn, E. J., Hu, B., Hunker, K., Johnson, A. D., Leusink, M., Lu, Y., ... Ganesh, S. K. (2016). Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. Nature Genetics, 48(8), 867-876. https://doi.org/10.1038/ng.3607

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

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.",

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

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journal = "Nature Genetics",

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Pankratz, N, Schick, UM, Zhou, Y, Zhou, W, Ahluwalia, TS, Allende, ML, Auer, PL, Bork-Jensen, J, Brody, JA, Chen, MH, Clavo, V, Eicher, JD, Grarup, N, Hagedorn, EJ, Hu, B, Hunker, K, Johnson, AD, Leusink, M, Lu, Y, Lyytikainen, LP, Manichaikul, A, Marioni, R, Nalls, MA, Pazoki, R, Smith, AV, Van Rooij, FJA, Yang, ML, Zhang, X, Zhang, Y, Asselbergs, FW, Boerwinkle, E, Borecki, IB, Bottinger, EP, Cushman, M, De Bakker, PIW, Deary, I, Dong, L, Feitosa, MF, Floyd, JS, Franceschini, N, Franco, OH, Garcia, ME, Grove, ML, Gudnason, V, Hansen, T, Harris, TB, Hofman, A, Jackson, RD, Jia, J, Kahonen, M, Launer, LJ, Lehtimaki, T, Liewald, D, Linneberg, A, Liu, Y, Loos, RJF, Nguyen, VM, Numans, ME, Pedersen, O, Psaty, BM, Raitakari, OT, Rich, SS, Rivadeneira, F, Di Sant, AMR, Rotter, JI, Starr, J, Taylor, KD, Thuesen, BH, Tracy, RP, Uitterlinden, AG, Wang, J, Wang, J, Dehghan, A, Huo, Y, Adrienne Cupples, L, Wilson, JG, Proia, RL, Zon, LI, O'Donnell, CJ, Reiner, AP & Ganesh, SK 2016, 'Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits', Nature Genetics, vol. 48, no. 8, pp. 867-876. https://doi.org/10.1038/ng.3607

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

AU - Ahluwalia, Tarunveer 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

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

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 - Jia, Jia

AU - Kahonen, Mika

AU - Launer, Lenore J.

AU - Lehtimaki, Terho

AU - Liewald, David

AU - Linneberg, Allan

AU - Liu, Yongmei

AU - Loos, Ruth J F

AU - Nguyen, Vy M.

AU - Numans, Mattijs E.

AU - Pedersen, Oluf

AU - Psaty, Bruce M.

AU - Raitakari, Olli T.

AU - Rich, Stephen S.

AU - Rivadeneira, Fernando

AU - Di Sant, Amanda M Rosa

AU - Rotter, Jerome I.

AU - Starr, John

AU - Taylor, Kent D.

AU - Thuesen, Betina Heinsbek

AU - Tracy, Russell P.

AU - Uitterlinden, Andre G.

AU - Wang, Jiansong

AU - Wang, Judy

AU - Dehghan, Abbas

AU - Huo, Yong

AU - Adrienne Cupples, L.

AU - Wilson, James G.

AU - Proia, Richard L.

AU - Zon, Leonard I.

AU - O'Donnell, Christopher J.

AU - Reiner, Alex P.

AU - Ganesh, Santhi K.

PY - 2016/8/1

Y1 - 2016/8/1

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.

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U2 - 10.1038/ng.3607

DO - 10.1038/ng.3607

M3 - Article

AN - SCOPUS:84978055882

SN - 1061-4036

VL - 48

SP - 867

EP - 876

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

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

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RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

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