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

A1 Refereed original research article in a scientific journal

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

Authors: Polfus LM, Khajuria RK, Schick UM, Pankratz N, Pazoki R, Brody JA, Chen MH, Auer PL, Floyd JS, Huang J, Lange L, van Rooij FJA, Gibbs RA, Metcalf G, Muzny D, Veeraraghavan N, Walter K, Chen L, Yanek L, Becker LC, Peloso GM, Wakabayashi A, Kals M, Metspalu A, Esko T, Fox K, Wallace R, Franceschini N, Matijevic N, Rice KM, Bartz TM, Lyytikainen LP, Kahonen M, Lehtimaki T, Raitakari OT, Li-Gao R, Mook-Kanamori DO, Lettre G, van Duijn CM, Franco OH, Rich SS, Rivadeneira F, Hofman A, Uitterlinden AG, Wilson JG, Psaty BM, Soranzo N, Dehghan A, Boerwinkle E, Zhang XL, Johnson AD, O'Donnell CJ, Johnsen JM, Reiner AP, Ganesh SK, Sankaran VG

Publisher: CELL PRESS

Publication year: 2016

Journal: American Journal of Human Genetics

Journal name in source: AMERICAN JOURNAL OF HUMAN GENETICS

Journal acronym: AM J HUM GENET

Volume: 99

Issue: 2

First page : 481

Last page: 488

Number of pages: 8

ISSN: 0002-9297

eISSN: 1537-6605

DOI: https://doi.org/10.1016/j.ajhg.2016.06.016

Abstract

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 x 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF=0.009, discovery + replication p=1.79 x 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.