Trans-ethnic meta-analysis of fetal hemoglobin genome-wide association results identifies common variants at the KLF1 locus. (Poster Presentation)


The clinical severity of sickle cell disease (SCD) and β-thalassemia, the major hemoglobinopathies that aff ect millions of patients worldwide, can be ameliorated by increased production of fetal hemoglobin (HbF). To date, genome-wide association studies have uncovered three main loci ( BCL11A, HBS1L-MYB, and the HBB locus) that modulate levels of HbF in hemoglobinopathy patients as well as non-anemic individuals. Together, genetic variation at these three loci accounts for ~50% of HbF heritability. To identify new HbF regulators, we performed a meta-analysis of genome-wide association results obtained from ~3,400 SCD patients of African ancestry and ~6000 healthy Sardinians. All association results were corrected for age, sex, and the main principal components, and were also conditioned on genotypes at BCL11A, HBS1L-MYB, and HBB. Meta-analysis results were well-calibrated (λ GC~1.0) and were not enriched among genetic variants that map to erythroid regulatory elements defi ned using DNAse 1 hypersensitive site assays, histone tail modifi cation profi ling, or ATAC-seq experiments. We identifie done novel genome-wide signifi cant locus on chromosome 19p13 (rs4804210, Pcombined=6.1x10-9, PSardiNIA=1.6x10-6, PSCD=6.4x10-4). HbF association results at this locus are independent from the previously reported HbF signal at the nearby NFIX gene (Danjou et al., Nature Genet., 2015). Using the GTEx resource, we found that rs4804210 (and its linkage disequilibrium proxies) is an eQTL for DNASE2 and KLF1. Further, this region physically interacts with the promoter of CALR as determined by Hi-C methodology. Although additional functional work is required, KLF1 represents a strong candidate causal gene at this locus: (1) it encodes a key erythroid transcription factor, (2) it is mutated in patients with hereditary persistence of fetal hemoglobin, and (3) it regulates the expression of BCL11A. Our results suggest that increasing sample size, even by combining individuals of diff erent ancestry, is a promising strategy to find loci associated with HbF levels, a critical modifi er of hemoglobin disease severity.

Oct 17, 2017 12:00 AM — Oct 21, 2017 12:00 AM
Orange County Convention Center, South Building
9800-9899 International Drive, Orlando, FL 32819