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

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Authors: 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 ; Andre´ G. Uitterlinden ; Oscar H. Franco ; Edith Hofer ; David Ginsburg ; Bella Hu ; Brendan Keating ; Ursula M. Schick ; Jennifer A. Brody ; Jun Z. Li

MeSH: Africa/ethnology ; Alleles ; Animals ; Bayes Theorem ; Continental Population Groups/genetics* ; Erythrocytes/metabolism* ; Erythropoiesis/genetics* ; Ethnic Groups/genetics ; Europe/ethnology ; Far East/ethnology ; Female ; Genome-Wide Association Study ; Humans ; Linkage Disequilibrium ; Male ; RNA-Binding Proteins/genetics* ; Zebrafish/genetics

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.