Dissecting the Genetic Architecture of Fetal Hemoglobin Expression

Abstract

Inducing production of fetal hemoglobin (HbF) is a promising therapeutic approach to ameliorate disease severity in beta-thalassemia and sickle cell disease. While studies have characterized individual genetic factors affecting fetal hemoglobin levels and begun to elucidate some underlying mechanisms, a complete understanding of how these elements interact to influence overall fetal hemoglobin expression levels has yet to be achieved. We hypothesize that varying range of fetal hemoglobin expression in the human population is the result of complex genetic architecture involving the interaction between multiple common and rare genetic variants. To interrogate the underlying genetic architecture of this complex and clinically-relevant trait, we have performed large genome-wide association study (GWAS) from two distinct study populations ascertained in different ways: a Thai population and a Swedish population. We genotyped all samples and implemented standard quality-control measures. From the samples and genotypes that passed quality control, we performed an association study for HbF levels using a linear mixed model instantiated through the BOLT-LMM tool. Our initial results have replicated known loci above genome-wide significance levels, including BCL11A, HBS1L-MYB, and HBB. Moreover, several novel loci and rare variants, including unique structural variants, appear to be present in our study. We are integrating whole genome sequencing on a subset of samples and in general population controls to better define these loci using imputation approaches, and we will account for the aggregate contribution of rare variants with large effects, including the structural variants we have identified. This work has tremendous promise to improve our understanding of how HbF levels can vary in populations, characterize underlying mechanisms by which this clinically important factor is regulated, and more generally elucidate how a range of allelic variants can collectively contribute to the genetic architecture of a complex trait.