Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis

Linda M. Polfus, Rajiv K. Khajuria, Ursula M. Schick, Nathan Pankratz, Raha Pazoki, Jennifer A. Brody, Ming Huei Chen, Paul L. Auer, James S. Floyd, Jie Huang, Leslie Lange, Frank J A van Rooij, Richard A. Gibbs, Ginger Metcalf, Donna Muzny, Narayanan Veeraraghavan, Klaudia Walter, Lu Chen, Lisa Yanek, Lewis C. BeckerGina M. Peloso, Aoi Wakabayashi, Mart Kals, Andres Metspalu, Tõnu Esko, Keolu Fox, Robert Wallace, Nora Franceshini, Nena Matijevic, Kenneth M. Rice, Traci M. Bartz, Leo Pekka Lyytikäinen, Mika Kähönen, Terho Lehtimäki, Olli T. Raitakari, Ruifang Li-Gao, Dennis O. Mook-Kanamori, Guillaume Lettre, Cornelia M. van Duijn, Oscar H. Franco, Stephen S. Rich, Fernando Rivadeneira, Albert Hofman, André G. Uitterlinden, James G. Wilson, Bruce M. Psaty, Nicole Soranzo, Abbas Dehghan, Eric Boerwinkle, Xiaoling Zhang, Andrew D. Johnson, Christopher J. O'Donnell, Jill M. Johnsen, Alexander P. Reiner, Santhi K. Ganesh, Vijay G. Sankaran

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10−10) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10−27). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis.

Original languageEnglish (US)
Pages (from-to)481-488
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Aug 4 2016

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© 2016 American Society of Human Genetics


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