PT - JOURNAL ARTICLE AU - Michael Guo AU - Satish K. Nandakumar AU - Jacob C. Ulirsch AU - Seyedeh Maryam Zekavat AU - Jason D. Buenrostro AU - Pradeep Natarajan AU - Rany Salem AU - Roberto Chiarle AU - Mario Mitt AU - Mart Kals AU - Kalle Pärn AU - Krista Fischer AU - Lili Milani AU - Reedik Mägi AU - Priit Palta AU - Stacey B. Gabriel AU - Andres Metspalu AU - Eric S. Lander AU - Sekar Kathiresan AU - Joel N. Hirschhorn AU - Tõnu Esko AU - Vijay G. Sankaran TI - Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms AID - 10.1101/067934 DP - 2016 Jan 01 TA - bioRxiv PG - 067934 4099 - http://biorxiv.org/content/early/2016/08/05/067934.short 4100 - http://biorxiv.org/content/early/2016/08/05/067934.full 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.