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A polygenic score for acute vaso-occlusive pain in pediatric sickle cell disease. Blood Adv 2021 07 27;5(14):2839-2851



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-85111179186   1 Citation


Individuals with monogenic disorders can experience variable phenotypes that are influenced by genetic variation. To investigate this in sickle cell disease (SCD), we performed whole-genome sequencing (WGS) of 722 individuals with hemoglobin HbSS or HbSβ0-thalassemia from Baylor College of Medicine and from the St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study. We developed pipelines to identify genetic variants that modulate sickle hemoglobin polymerization in red blood cells and combined these with pain-associated variants to build a polygenic score (PGS) for acute vaso-occlusive pain (VOP). Overall, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10-14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10-13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.

Author List

Rampersaud E, Kang G, Palmer LE, Rashkin SR, Wang S, Bi W, Alberts NM, Anghelescu D, Barton M, Birch K, Boulos N, Brandow AM, Brooke RJ, Chang TC, Chen W, Cheng Y, Ding J, Easton J, Hodges JR, Kanne CK, Levy S, Mulder H, Patel AP, Puri L, Rosencrance C, Rusch M, Sapkota Y, Sioson E, Sharma A, Tang X, Thrasher A, Wang W, Yao Y, Yasui Y, Yergeau D, Hankins JS, Sheehan VA, Downing JR, Estepp JH, Zhang J, DeBaun M, Wu G, Weiss MJ


Amanda Brandow DO Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anemia, Sickle Cell
Fetal Hemoglobin
Longitudinal Studies
Polymorphism, Single Nucleotide