A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis
Tekijät: 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
Kustantaja: CELL PRESS
Julkaisuvuosi: 2016
Journal: American Journal of Human Genetics
Tietokannassa oleva lehden nimi: AMERICAN JOURNAL OF HUMAN GENETICS
Lehden akronyymi: AM J HUM GENET
Vuosikerta: 99
Numero: 2
Aloitussivu: 481
Lopetussivu: 488
Sivujen määrä: 8
ISSN: 0002-9297
eISSN: 1537-6605
DOI: https://doi.org/10.1016/j.ajhg.2016.06.016
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.
