Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Michael H. Guoa, Satish K. Nandakumar, Jacob C. Ulirsch, Seyedeh M. Zekavat, Jason D. Buenrostro, Pradeep Natarajan, Rany M. Salem, Roberto Chiarle, Mario Mitt, Mart Kals, Kalle Pärn, Krista Fischer, Lili Milani, Reedik Mägi, Priit Palta, Stacey B. Gabriel, Andres Metspalu, Eric S. Lander, Sekar Kathiresan, Joel N. HirschhornTõnu Esko, Vijay G. Sankaran

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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 highcoverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil countassociated 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.

Original languageEnglish (US)
Pages (from-to)E327-E336
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 17 2017
Externally publishedYes


  • Basophils
  • GWAS
  • Genome sequencing
  • Hematopoiesis

ASJC Scopus subject areas

  • General


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