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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 publication

DOI

10.1016/j.ajhg.2016.06.016

Type

Journal article

Journal

Am J Hum Genet

Publication Date

04/08/2016

Volume

99

Pages

481 - 488

Keywords

Alternative Splicing, Blood Platelets, CRISPR-Cas Systems, DNA Mutational Analysis, Exome, Gene Editing, Genetic Loci, Hematopoiesis, Hematopoietic Stem Cells, Humans, Megakaryocytes, Platelet Count, Proto-Oncogene Proteins, Repressor Proteins