Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Frank J.A. van Rooij; Rehan Qayyum; Albert V. Smith; Yi Zhou; Stella Trompet; Toshiko Tanaka; Margaux F. Keller; Li Ching Chang; Helena Schmidt; Min Lee Yang; Ming Huei Chen; James Hayes; Andrew D. Johnson; Lisa R. Yanek; Christian Mueller; Leslie Lange; James S. Floyd; Mohsen Ghanbari; Alan B. Zonderman; J. Wouter Jukema; Albert Hofman; Cornelia M. van Duijn; Karl C. Desch; Yasaman Saba; Ayse B. Ozel; Beverly M. Snively; Jer Yuarn Wu; Reinhold Schmidt; Myriam Fornage; Robert J. Klein; Caroline S. Fox; Koichi Matsuda; Naoyuki Kamatani; Philipp S. Wild; David J. Stott; Ian Ford; P. Eline Slagboom; Jaden Yang; Audrey Y. Chu; Amy J. Lambert; André G. Uitterlinden; Oscar H. Franco; Edith Hofer; David Ginsburg; Bella Hu; Brendan Keating; Ursula M. Schick; Jennifer A. Brody; Jun Z. Li; Zhao Chen; Tanja Zeller; Jack M. Guralnik; Daniel I. Chasman; Luanne L. Peters; Michiaki Kubo; Diane M. Becker; Jin Li; Gudny Eiriksdottir; Jerome I. Rotter; Daniel Levy; Vera Grossmann; Kushang V. Patel; Chien Hsiun Chen; Paul M. Ridker; Hua Tang; Lenore J. Launer; Kenneth M. Rice; Ruifang Li-Gao; Luigi Ferrucci; Michelle K. Evans; Avik Choudhuri; Eirini Trompouki; Brian J. Abraham; Song Yang; Atsushi Takahashi; Yoichiro Kamatani; Charles Kooperberg; Tamara B. Harris; Sun Ha Jee; Josef Coresh; Fuu Jen Tsai; Dan L. Longo; Yuan Tsong Chen; Janine F. Felix; Qiong Yang; Bruce M. Psaty; Eric Boerwinkle; Lewis C. Becker; Dennis O. Mook-Kanamori; James G. Wilson; Vilmundur Gudnason; Christopher J. O'Donnell; Abbas Dehghan; L. Adrienne Cupples; Michael A. Nalls; Andrew P. Morris; Yukinori Okada; Alexander P. Reiner; Leonard I. Zon; Santhi K. Ganesh

doi:10.1016/j.ajhg.2016.11.016

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Frank J.A. van Rooij, Rehan Qayyum, Albert V. Smith, Yi Zhou, Stella Trompet, Toshiko Tanaka, Margaux F. Keller, Li Ching Chang, Helena Schmidt, Min Lee Yang, Ming Huei Chen, James Hayes, Andrew D. Johnson, Lisa R. Yanek, Christian Mueller, Leslie Lange, James S. Floyd, Mohsen Ghanbari, Alan B. Zonderman, J. Wouter JukemaAlbert Hofman, Cornelia M. van Duijn, Karl C. Desch, Yasaman Saba, Ayse B. Ozel, Beverly M. Snively, Jer Yuarn Wu, Reinhold Schmidt, Myriam Fornage, Robert J. Klein, Caroline S. Fox, Koichi Matsuda, Naoyuki Kamatani, Philipp S. Wild, David J. Stott, Ian Ford, P. Eline Slagboom, Jaden Yang, Audrey Y. Chu, Amy J. Lambert, André G. Uitterlinden, Oscar H. Franco, Edith Hofer, David Ginsburg, Bella Hu, Brendan Keating, Ursula M. Schick, Jennifer A. Brody, Jun Z. Li, Zhao Chen, Tanja Zeller, Jack M. Guralnik, Daniel I. Chasman, Luanne L. Peters, Michiaki Kubo, Diane M. Becker, Jin Li, Gudny Eiriksdottir, Jerome I. Rotter, Daniel Levy, Vera Grossmann, Kushang V. Patel, Chien Hsiun Chen, Paul M. Ridker, Hua Tang, Lenore J. Launer, Kenneth M. Rice, Ruifang Li-Gao, Luigi Ferrucci, Michelle K. Evans, Avik Choudhuri, Eirini Trompouki, Brian J. Abraham, Song Yang, Atsushi Takahashi, Yoichiro Kamatani, Charles Kooperberg, Tamara B. Harris, Sun Ha Jee, Josef Coresh, Fuu Jen Tsai, Dan L. Longo, Yuan Tsong Chen, Janine F. Felix, Qiong Yang, Bruce M. Psaty, Eric Boerwinkle, Lewis C. Becker, Dennis O. Mook-Kanamori, James G. Wilson, Vilmundur Gudnason, Christopher J. O'Donnell, Abbas Dehghan, L. Adrienne Cupples, Michael A. Nalls, Andrew P. Morris, Yukinori Okada, Alexander P. Reiner, Leonard I. Zon, Santhi K. Ganesh

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Abstract

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

Original language	English (US)
Pages (from-to)	51-63
Number of pages	13
Journal	American Journal of Human Genetics
Volume	100
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2016.11.016
State	Published - Jan 5 2017

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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van Rooij, F. J. A., Qayyum, R., Smith, A. V., Zhou, Y., Trompet, S., Tanaka, T., Keller, M. F., Chang, L. C., Schmidt, H., Yang, M. L., Chen, M. H., Hayes, J., Johnson, A. D., Yanek, L. R., Mueller, C., Lange, L., Floyd, J. S., Ghanbari, M., Zonderman, A. B., ... Ganesh, S. K. (2017). Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. American Journal of Human Genetics, 100(1), 51-63. https://doi.org/10.1016/j.ajhg.2016.11.016

van Rooij, FJA, Qayyum, R, Smith, AV, Zhou, Y, Trompet, S, Tanaka, T, Keller, MF, Chang, LC, Schmidt, H, Yang, ML, Chen, MH, Hayes, J, Johnson, AD, Yanek, LR, Mueller, C, Lange, L, Floyd, JS, Ghanbari, M, Zonderman, AB, Jukema, JW, Hofman, A, van Duijn, CM, Desch, KC, Saba, Y, Ozel, AB, Snively, BM, Wu, JY, Schmidt, R, Fornage, M, Klein, RJ, Fox, CS, Matsuda, K, Kamatani, N, Wild, PS, Stott, DJ, Ford, I, Slagboom, PE, Yang, J, Chu, AY, Lambert, AJ, Uitterlinden, AG, Franco, OH, Hofer, E, Ginsburg, D, Hu, B, Keating, B, Schick, UM, Brody, JA, Li, JZ, Chen, Z, Zeller, T, Guralnik, JM, Chasman, DI, Peters, LL, Kubo, M, Becker, DM, Li, J, Eiriksdottir, G, Rotter, JI, Levy, D, Grossmann, V, Patel, KV, Chen, CH, Ridker, PM, Tang, H, Launer, LJ, Rice, KM, Li-Gao, R, Ferrucci, L, Evans, MK, Choudhuri, A, Trompouki, E, Abraham, BJ, Yang, S, Takahashi, A, Kamatani, Y, Kooperberg, C, Harris, TB, Jee, SH, Coresh, J, Tsai, FJ, Longo, DL, Chen, YT, Felix, JF, Yang, Q, Psaty, BM, Boerwinkle, E, Becker, LC, Mook-Kanamori, DO, Wilson, JG, Gudnason, V, O'Donnell, CJ, Dehghan, A, Cupples, LA, Nalls, MA, Morris, AP, Okada, Y, Reiner, AP, Zon, LI & Ganesh, SK 2017, 'Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis', American Journal of Human Genetics, vol. 100, no. 1, pp. 51-63. https://doi.org/10.1016/j.ajhg.2016.11.016

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title = "Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis",

abstract = "Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.",

author = "{van Rooij}, {Frank J.A.} and Rehan Qayyum and Smith, {Albert V.} and Yi Zhou and Stella Trompet and Toshiko Tanaka and Keller, {Margaux F.} and Chang, {Li Ching} and Helena Schmidt and Yang, {Min Lee} and Chen, {Ming Huei} and James Hayes and Johnson, {Andrew D.} and Yanek, {Lisa R.} and Christian Mueller and Leslie Lange and Floyd, {James S.} and Mohsen Ghanbari and Zonderman, {Alan B.} and Jukema, {J. Wouter} and Albert Hofman and {van Duijn}, {Cornelia M.} and Desch, {Karl C.} and Yasaman Saba and Ozel, {Ayse B.} and Snively, {Beverly M.} and Wu, {Jer Yuarn} and Reinhold Schmidt and Myriam Fornage and Klein, {Robert J.} and Fox, {Caroline S.} and Koichi Matsuda and Naoyuki Kamatani and Wild, {Philipp S.} and Stott, {David J.} and Ian Ford and Slagboom, {P. Eline} and Jaden Yang and Chu, {Audrey Y.} and Lambert, {Amy J.} and Uitterlinden, {Andr{\'e} G.} and Franco, {Oscar H.} and Edith Hofer and David Ginsburg and Bella Hu and Brendan Keating and Schick, {Ursula M.} and Brody, {Jennifer A.} and Li, {Jun Z.} and Zhao Chen and Tanja Zeller and Guralnik, {Jack M.} and Chasman, {Daniel I.} and Peters, {Luanne L.} and Michiaki Kubo and Becker, {Diane M.} and Jin Li and Gudny Eiriksdottir and Rotter, {Jerome I.} and Daniel Levy and Vera Grossmann and Patel, {Kushang V.} and Chen, {Chien Hsiun} and Ridker, {Paul M.} and Hua Tang and Launer, {Lenore J.} and Rice, {Kenneth M.} and Ruifang Li-Gao and Luigi Ferrucci and Evans, {Michelle K.} and Avik Choudhuri and Eirini Trompouki and Abraham, {Brian J.} and Song Yang and Atsushi Takahashi and Yoichiro Kamatani and Charles Kooperberg and Harris, {Tamara B.} and Jee, {Sun Ha} and Josef Coresh and Tsai, {Fuu Jen} and Longo, {Dan L.} and Chen, {Yuan Tsong} and Felix, {Janine F.} and Qiong Yang and Psaty, {Bruce M.} and Eric Boerwinkle and Becker, {Lewis C.} and Mook-Kanamori, {Dennis O.} and Wilson, {James G.} and Vilmundur Gudnason and O'Donnell, {Christopher J.} and Abbas Dehghan and Cupples, {L. Adrienne} and Nalls, {Michael A.} and Morris, {Andrew P.} and Yukinori Okada and Reiner, {Alexander P.} and Zon, {Leonard I.} and Ganesh, {Santhi K.}",

note = "Publisher Copyright: {\textcopyright} 2017 American Society of Human Genetics",

year = "2017",

month = jan,

day = "5",

doi = "10.1016/j.ajhg.2016.11.016",

language = "English (US)",

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pages = "51--63",

journal = "American Journal of Human Genetics",

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TY - JOUR

T1 - Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

AU - van Rooij, Frank J.A.

AU - Qayyum, Rehan

AU - Smith, Albert V.

AU - Zhou, Yi

AU - Trompet, Stella

AU - Tanaka, Toshiko

AU - Keller, Margaux F.

AU - Chang, Li Ching

AU - Schmidt, Helena

AU - Yang, Min Lee

AU - Chen, Ming Huei

AU - Hayes, James

AU - Johnson, Andrew D.

AU - Yanek, Lisa R.

AU - Mueller, Christian

AU - Lange, Leslie

AU - Floyd, James S.

AU - Ghanbari, Mohsen

AU - Zonderman, Alan B.

AU - Jukema, J. Wouter

AU - Hofman, Albert

AU - van Duijn, Cornelia M.

AU - Desch, Karl C.

AU - Saba, Yasaman

AU - Ozel, Ayse B.

AU - Snively, Beverly M.

AU - Wu, Jer Yuarn

AU - Schmidt, Reinhold

AU - Fornage, Myriam

AU - Klein, Robert J.

AU - Fox, Caroline S.

AU - Matsuda, Koichi

AU - Kamatani, Naoyuki

AU - Wild, Philipp S.

AU - Stott, David J.

AU - Ford, Ian

AU - Slagboom, P. Eline

AU - Yang, Jaden

AU - Chu, Audrey Y.

AU - Lambert, Amy J.

AU - Uitterlinden, André G.

AU - Franco, Oscar H.

AU - Hofer, Edith

AU - Ginsburg, David

AU - Hu, Bella

AU - Keating, Brendan

AU - Schick, Ursula M.

AU - Brody, Jennifer A.

AU - Li, Jun Z.

AU - Chen, Zhao

AU - Zeller, Tanja

AU - Guralnik, Jack M.

AU - Chasman, Daniel I.

AU - Peters, Luanne L.

AU - Kubo, Michiaki

AU - Becker, Diane M.

AU - Li, Jin

AU - Eiriksdottir, Gudny

AU - Rotter, Jerome I.

AU - Levy, Daniel

AU - Grossmann, Vera

AU - Patel, Kushang V.

AU - Chen, Chien Hsiun

AU - Ridker, Paul M.

AU - Tang, Hua

AU - Launer, Lenore J.

AU - Rice, Kenneth M.

AU - Li-Gao, Ruifang

AU - Ferrucci, Luigi

AU - Evans, Michelle K.

AU - Choudhuri, Avik

AU - Trompouki, Eirini

AU - Abraham, Brian J.

AU - Yang, Song

AU - Takahashi, Atsushi

AU - Kamatani, Yoichiro

AU - Kooperberg, Charles

AU - Harris, Tamara B.

AU - Jee, Sun Ha

AU - Coresh, Josef

AU - Tsai, Fuu Jen

AU - Longo, Dan L.

AU - Chen, Yuan Tsong

AU - Felix, Janine F.

AU - Yang, Qiong

AU - Psaty, Bruce M.

AU - Boerwinkle, Eric

AU - Becker, Lewis C.

AU - Mook-Kanamori, Dennis O.

AU - Wilson, James G.

AU - Gudnason, Vilmundur

AU - O'Donnell, Christopher J.

AU - Dehghan, Abbas

AU - Cupples, L. Adrienne

AU - Nalls, Michael A.

AU - Morris, Andrew P.

AU - Okada, Yukinori

AU - Reiner, Alexander P.

AU - Zon, Leonard I.

AU - Ganesh, Santhi K.

PY - 2017/1/5

Y1 - 2017/1/5

N2 - Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

AB - Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

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U2 - 10.1016/j.ajhg.2016.11.016

DO - 10.1016/j.ajhg.2016.11.016

M3 - Article

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AN - SCOPUS:85009756485

SN - 0002-9297

VL - 100

SP - 51

EP - 63

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

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