Andrew M Heitzer1, Jennifer Longoria2, Evadnie Rampersaud3, Sara R Rashkin4, Jeremie H Estepp5, Victoria I Okhomina6, Winfred C Wang5, Darcy Raches2, Brian Potter2, Martin H Steinberg7, Allison A King8, Guolian Kang9, Jane S Hankins5. 1. Departments of Psychology, St. Jude Children's Research Hospital, Memphis, TN. Electronic address: aheitzer@stjude.org. 2. Departments of Psychology, St. Jude Children's Research Hospital, Memphis, TN. 3. Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN. 4. Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN; Hematology, St. Jude Children's Research Hospital, Memphis, TN. 5. Hematology, St. Jude Children's Research Hospital, Memphis, TN. 6. Biostatistics, St. Jude Children's Research Hospital, Memphis, TN. 7. Department of Medicine, Boston University School of Medicine, Boston, MA. 8. Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University, St. Louis, MO. 9. Biostatistics, St. Jude Children's Research Hospital, Memphis, TN; Departments of Psychology, St. Jude Children's Research Hospital, Memphis, TN.
Abstract
PURPOSE OF THE STUDY: Fetal hemoglobin (HbF) is a modifier of the clinical and hematologic phenotype of sickle cell anemia (SCA). Three quantitative trait loci (QTL) modulate HbF expression. The neurocognitive effects of variants in these QTL have yet to be explored. We evaluated the relation between 11 SNPs in the three HbF QTL: BCL11A, MYB, the HBB gene cluster, and full-scale intelligence (IQ) in SCA. PATIENTS AND METHODS: The prospective longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program, was used as a discovery cohort (n = 166). The genotypes for 11 SNPs were extracted through whole genome sequencing and were analyzed using an additive model. A polygenic score for HbF (PGSHbF) integrating the numbers of low HbF alleles from 11 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (n = 156) and the Silent Cerebral Infarction Transfusion (n = 114) Trial were used as two independent replication cohorts. Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (pFDR). RESULTS: HbF was positively associated with IQ (minimum raw p = 0·0018) at pFDR<0·05. HbF mediated the relationship between two BCL11A SNPs, rs1427407 and rs7606173, HBS1L-MYB: rs9494142, and PGSHbF with IQ (minimum raw p = 0·0035) at pFDR<0·05. CONCLUSION: As the major modulator of the severity of SCA, HbF also influences neurocognition, which is done through mediation of its QTL. These findings have implications for early identification of neurocognitive risk and targeted intervention.
PURPOSE OF THE STUDY: Fetal hemoglobin (HbF) is a modifier of the clinical and hematologic phenotype of sickle cell anemia (SCA). Three quantitative trait loci (QTL) modulate HbF expression. The neurocognitive effects of variants in these QTL have yet to be explored. We evaluated the relation between 11 SNPs in the three HbF QTL: BCL11A, MYB, the HBB gene cluster, and full-scale intelligence (IQ) in SCA. PATIENTS AND METHODS: The prospective longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program, was used as a discovery cohort (n = 166). The genotypes for 11 SNPs were extracted through whole genome sequencing and were analyzed using an additive model. A polygenic score for HbF (PGSHbF) integrating the numbers of low HbF alleles from 11 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (n = 156) and the Silent Cerebral Infarction Transfusion (n = 114) Trial were used as two independent replication cohorts. Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (pFDR). RESULTS: HbF was positively associated with IQ (minimum raw p = 0·0018) at pFDR<0·05. HbF mediated the relationship between two BCL11A SNPs, rs1427407 and rs7606173, HBS1L-MYB: rs9494142, and PGSHbF with IQ (minimum raw p = 0·0035) at pFDR<0·05. CONCLUSION: As the major modulator of the severity of SCA, HbF also influences neurocognition, which is done through mediation of its QTL. These findings have implications for early identification of neurocognitive risk and targeted intervention.
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Authors: Evadnie Rampersaud; Guolian Kang; Lance E Palmer; Sara R Rashkin; Shuoguo Wang; Wenjian Bi; Nicole M Alberts; Doralina Anghelescu; Martha Barton; Kirby Birch; Nidal Boulos; Amanda M Brandow; Russell John Brooke; Ti-Cheng Chang; Wenan Chen; Yong Cheng; Juan Ding; John Easton; Jason R Hodges; Celeste K Kanne; Shawn Levy; Heather Mulder; Ashwin P Patel; Latika Puri; Celeste Rosencrance; Michael Rusch; Yadav Sapkota; Edgar Sioson; Akshay Sharma; Xing Tang; Andrew Thrasher; Winfred Wang; Yu Yao; Yutaka Yasui; Donald Yergeau; Jane S Hankins; Vivien A Sheehan; James R Downing; Jeremie H Estepp; Jinghui Zhang; Michael DeBaun; Gang Wu; Mitchell J Weiss Journal: Blood Adv Date: 2021-07-27