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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 languageEnglish
Pages (from-to)51-63
Number of pages13
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
Publication statusPublished - 05-01-2017

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Genetic Loci
Erythropoiesis
Genome-Wide Association Study
Meta-Analysis
Erythrocyte Indices
Erythrocytes
Genome
Morpholinos
Bayes Theorem
Linkage Disequilibrium
Zebrafish
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

van Rooij, Frank J.A. ; Qayyum, Rehan ; Smith, Albert V. ; Zhou, Yi ; Trompet, Stella ; Tanaka, Toshiko ; Keller, Margaux F. ; Chang, Li Ching ; Schmidt, Helena ; Yang, Min Lee ; Chen, Ming Huei ; Hayes, James ; Johnson, Andrew D. ; Yanek, Lisa R. ; Mueller, Christian ; Lange, Leslie ; Floyd, James S. ; Ghanbari, Mohsen ; Zonderman, Alan B. ; Jukema, J. Wouter ; Hofman, Albert ; van Duijn, Cornelia M. ; Desch, Karl C. ; Saba, Yasaman ; Ozel, Ayse B. ; Snively, Beverly M. ; Wu, Jer Yuarn ; Schmidt, Reinhold ; Fornage, Myriam ; Klein, Robert J. ; Fox, Caroline S. ; Matsuda, Koichi ; Kamatani, Naoyuki ; Wild, Philipp S. ; Stott, David J. ; Ford, Ian ; Slagboom, P. Eline ; Yang, Jaden ; Chu, Audrey Y. ; Lambert, Amy J. ; Uitterlinden, André G. ; Franco, Oscar H. ; Hofer, Edith ; Ginsburg, David ; Hu, Bella ; Keating, Brendan ; Schick, Ursula M. ; Brody, Jennifer A. ; Li, Jun Z. ; Chen, Zhao ; Zeller, Tanja ; Guralnik, Jack M. ; Chasman, Daniel I. ; Peters, Luanne L. ; Kubo, Michiaki ; Becker, Diane M. ; Li, Jin ; Eiriksdottir, Gudny ; Rotter, Jerome I. ; Levy, Daniel ; Grossmann, Vera ; Patel, Kushang V. ; Chen, Chien Hsiun ; Ridker, Paul M. ; Tang, Hua ; Launer, Lenore J. ; Rice, Kenneth M. ; Li-Gao, Ruifang ; Ferrucci, Luigi ; Evans, Michelle K. ; Choudhuri, Avik ; Trompouki, Eirini ; Abraham, Brian J. ; Yang, Song ; Takahashi, Atsushi ; Kamatani, Yoichiro ; Kooperberg, Charles ; Harris, Tamara B. ; Jee, Sun Ha ; Coresh, Josef ; Tsai, Fuu Jen ; Longo, Dan L. ; Chen, Yuan Tsong ; Felix, Janine F. ; Yang, Qiong ; Psaty, Bruce M. ; Boerwinkle, Eric ; Becker, Lewis C. ; Mook-Kanamori, Dennis O. ; Wilson, James G. ; Gudnason, Vilmundur ; O'Donnell, Christopher J. ; Dehghan, Abbas ; Cupples, L. Adrienne ; Nalls, Michael A. ; Morris, Andrew P. ; Okada, Yukinori ; Reiner, Alexander P. ; Zon, Leonard I. ; Ganesh, Santhi K. / Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 1. pp. 51-63.
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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.",
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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

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

In: American Journal of Human Genetics, Vol. 100, No. 1, 05.01.2017, p. 51-63.

Research output: Contribution to journalArticle

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

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AN - SCOPUS:85009756485

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SP - 51

EP - 63

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

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