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 languageEnglish (US)
Pages (from-to)51-63
Number of pages13
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
StatePublished - Jan 5 2017

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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