Functional dissection of the gene regulatory mechanism underlying variation in blood CD34+ cell levels at 1p36.23/ENO1

Understanding the genetic regulation of blood CD34⁺ cell levels could lead to better methods for stem cell mobilization and transplantation. Recently, in a genome-wide association study (GWAS), we identified 11 genetic associations with blood CD34⁺ cell levels. One of the most significant maps to an intergenic region between the ENO1 and RERE genes at chromosome 1p36.23. However, the underlying mechanism remains unknown. Here, using functional fine-mapping, we identify rs10864368:C > T as a causal non-coding variant. Specifically, the rs10864368-T allele abrogates a binding site for the GATA2 transcription factor, leading to downregulation of ENO1 and RERE and lower CD34⁺ cell levels. Our data link a specific GATA2 target to the regulation of CD34⁺ cell levels, expanding on the role of GATA2 in human hematopoieisis.