Heritability of fetal hemoglobin, white cell count, and other clinical traits from a sickle cell disease family cohort

Abstract

Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family-based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family-based studies to better understand modifiers of SCD.

Figure 1:. Effects of 5 risk factors on 11 markers of sickle cell morbidity.

Odds ratios (OR) and 95% confidence interval bounds for the effects of high (A) fetal hemoglobin, (B) white blood cell count (WBC), (C) hematocrit, (D) systolic blood pressure, (E) and cigarette smoking on 11 markers of SCD morbidity: low hematocrit, history of blood transfusions, pain crisis, acute chest syndrome, high WBC, leg ulcers, aseptic necrosis of the hip or shoulder, priapism, retinopathy, cholecystectomy, and stroke. Estimates were derived from a logistic regression model, adjusting for age and sex. In order to scale all outcomes such that a higher OR indicates increased morbidity, the outcome for hematocrit was reversed (i.e., an association with low hematocrit corresponds to an OR > 1). Yellow shading indicates nominal significance (p < 0.05); red indicates significance after adjusting for false discovery rate (FDR-adjusted p < 0.05).

Figure 2:. Measuring the heritability and shared genetic influences of fetal hemoglobin and white blood cell count.

(A) Heritability estimates of 20 clinical hematologic traits determined by variance components analysis. Genetic correlations between (B) fetal hemoglobin and (C) white blood cell count compared to other hematologic traits. Yellow shading indicates nominal significance (p < 0.05); red indicates significance after adjusting for false discovery rate (FDR-adjusted p < 0.05). Abbreviations: baso, basophil count; BP, systolic blood pressure; eos, eosinophil count; HbA, hemoglobin A; HbA2, hemoglobin A2; Hct, hematocrit; Hgb, hemoglobin; HbF, fetal hemoglobin; HR, heart rate; HbS, hemoglobin S; lymph, lymphocyte count; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; mono, monocyte count; MPV, mean platelet volume; PLT, platelet count; poly, polymorphonuclear leukocyte count; RBC, red blood cell count; ret, reticulocyte count; WBC, white blood cell count.