Purpose of review: The discovery of several genetic variants associated with erythroid traits and subsequent elucidation of their functional mechanisms are exemplars of the power of the new genetic and genomic technology. The present review highlights findings from recent genetic studies related to the control of erythropoiesis and dyserythropoiesis, and fetal hemoglobin, an erythroid-related trait.
Recent findings: Identification of the genetic modulators of erythropoiesis involved two approaches: genome-wide association studies (GWASs) using single nucleotide polymorphism (SNP) arrays that revealed the common genetic variants associated with erythroid phenotypes (hemoglobin, red cell count, MCV, MCH) and fetal hemoglobin; and massive parallel sequencing such as whole genome sequencing (WGS) and whole exome sequencing (WES) that led to the discovery of the rarer variants (GFI1B, SBDS, RPS19, PKLR, EPO, EPOR, KLF1, GATA1). Functional and genomic studies aided by computational approaches and gene editing technology refined the regions encompassing the putative causative SNPs and confirmed their regulatory role at different stages of erythropoiesis.
Summary: Five meta-analysis of GWASs identified 17 genetic loci associated with erythroid phenotypes, which are potential regulators of erythropoiesis. Some of these loci showed pleiotropy associated with multiple erythroid traits, suggesting undiscovered molecular mechanisms and challenges underlying erythroid biology. Other sequencing strategies (WGS and WES) further elucidated the role of rare variants in dyserythropoiesis. Integration of common and rare variant studies with functional assays involving latest genome-editing technologies will significantly improve our understanding of the genetics underlying erythropoiesis and erythroid disorders.