RT Journal Article
SR Electronic
T1 Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 067934
DO 10.1101/067934
A1 Michael Guo
A1 Satish K. Nandakumar
A1 Jacob C. Ulirsch
A1 Seyedeh Maryam Zekavat
A1 Jason D. Buenrostro
A1 Pradeep Natarajan
A1 Rany Salem
A1 Roberto Chiarle
A1 Mario Mitt
A1 Mart Kals
A1 Kalle Pärn
A1 Krista Fischer
A1 Lili Milani
A1 Reedik Mägi
A1 Priit Palta
A1 Stacey B. Gabriel
A1 Andres Metspalu
A1 Eric S. Lander
A1 Sekar Kathiresan
A1 Joel N. Hirschhorn
A1 Tõnu Esko
A1 Vijay G. Sankaran
YR 2016
UL http://biorxiv.org/content/early/2016/08/04/067934.abstract
AB Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high coverage whole genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional ~17,000 samples. Our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic data sets provided evidence for causal mechanisms at several loci, including at a novel basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.