A Phenome-wide Association Study of Polygenic Scores for Selected Childhood Cancer: Results from The UK Biobank.

The aim of this study was to scan phenotypes in adulthood associated with polygenic risk scores (PRS) for childhood cancers with well-articulated genetic architectures: acute lymphoblastic leukemia (ALL), Ewing sarcoma, and neuroblastoma to examine genetic pleiotropy. Furthermore, we aimed to determine which single nucleotide polymorphisms (SNPs) could drive associations. Per-SNP summary statistics were extracted for PRS calculation. Participants with white British ancestry were exclusively included for analyses. SNPs were queried from the UK biobank genotype imputation data. Records from the cancer registry, death registry, and inpatient diagnoses were abstracted for phenome-wide scans. Firth logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) alongside corresponding p-values, adjusting for age at recruitment and sex. A total of 244,332 unrelated white British participants were included. We observed a significant association between ALL-PRS and ALL (OR: 1.20e+24, 95% CI: 9.08e+14-1.60e+33). In addition, we observed a significant association between high-risk neuroblastoma PRS and nonrheumatic aortic valve disorders (OR: 43.9, 95% CI: 7.42-260). There were no significant phenotype associations with Ewing sarcoma and neuroblastoma PRS. Regarding individual SNPs, rs17607816 increased the risk of ALL (OR: 6.40, 95% CI: 3.26-12.57). For high-risk neuroblastoma, rs80059929 elevated the risk of atrioventricular block (OR: 3.04, 95% CI: 1.85-4.99). Our findings suggest that individuals with genetic susceptibility to ALL may face a lifelong risk for developing ALL, along with a genetic pleiotropic association between high-risk neuroblastoma and circulatory diseases.

Genetic analyses identify evidence for a causal relationship between Ewing sarcoma and hernias.

Knowledge of Ewing sarcoma (EWS) risk factors is exceedingly limited; however, multiple small, independent studies have suggested a possible connection between hernia and EWS. By leveraging hernia summary statistics from the UK Biobank and a recently published genome-wide association study of EWS (733 EWS cases and 1,346 controls), we conducted a genetic investigation of the relationship of 5 hernia types (diaphragmatic, inguinal, umbilical, femoral, and ventral) and EWS. We discovered a positive causal relationship between inguinal hernia and EWS (OR 1.27, 95% confidence interval [CI] 1.01-1.59, and p = 0.041) through Mendelian randomization analysis. Further analyses suggested shared pathways through three genes: HMGA2, LOX, and FBXW7. Diaphragmatic hernia showed a stronger causal relationship with EWS among all of the hernia types (OR 2.26, 95% CI 1.30-3.95, p = 0.004), but no statistically significant local correlation pattern was observed. No evidence of a causal or genetic relationship was observed between EWS and the other three hernia types, including umbilical hernia, despite a previous report indicating an OR as high as 3.3. The finding of our genetic analysis provided additional support to the hypothesis that EWS and hernias may share a common origin.

Genetic ancestry, differential gene expression, and survival in pediatric B-cell acute lymphoblastic leukemia.

BACKGROUND: Black children have lower incidence yet worse survival than White and Latinx children with B-cell acute lymphoblastic leukemia (B-ALL). It is unclear how reported race/ethnicity (RRE) is associated with death in B-ALL after accounting for differentially expressed genes associated with genetic ancestry. METHODS: Using Phase 1 and 2 NCI TARGET B-ALL cases (N = 273; RRE-Black = 21, RRE-White = 162, RRE-Latinx = 69, RRE-Other = 9, RRE-Unknown = 12), we estimated proportions of African (AFR), European (EUR), and Amerindian (AMR) genetic ancestry. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) between ancestry and death while adjusting for RRE and clinical measures. We identified genes associated with genetic ancestry and adjusted for them in RRE and death associations. RESULTS: Genetic ancestry varied within RRE (RRE-Black, AFR proportion: Mean: 78.5%, Range: 38.2%-93.6%; RRE-White, EUR proportion: Mean: 94%, Range: 1.6%-99.9%; RRE-Latinx, AMR proportion: Mean: 52.0%, Range: 1.2%-98.7%). We identified 10, 1, and 6 differentially expressed genes (padjusted  <0.05) associated with AFR, AMR, and EUR ancestry proportion, respectively. We found AMR and AFR ancestry were statistically significantly associated with death (AMR each 10% HR: 1.05, 95% CI: 1.03-1.17, AFR each 10% increase HR: 1.03, 95% CI:1.01-1.19). RRE differences in the risk of death were larger in magnitude upon adjustment for genes associated with genetic ancestry for RRE-Black, but not RRE-Latinx children (RRE-Black HR: 3.35, 95% CI: 1.31, 8.53; RRE-Latinx HR: 1.47, 0.88-2.45). CONCLUSIONS: Our work highlights B-ALL survival differences by RRE after adjusting for ancestry differentially expressed genes suggesting other factors impacting survival are important.

Impact of fetal expression quantitative trait loci on transcriptome-wide association study of childhood leukemia.

Transcriptome-wide association studies increase the yield of loci associated with disease phenotypes by focusing on expression quantitative trait loci (eQTL). The major source of eQTL data for is the Gene and Tissue Expression (GTEx) project, which is comprised entirely of adults, mainly those >50 years of age at death. Since gene expression levels differ by developmental stage, it is not clear whether eQTLs derived from adult data sources are best suited for use in young-onset diseases such as pediatric cancers. To fill in this knowledge gap, we performed a large-scale eQTL mapping analysis in the GenCord study with newborn samples and compared it with GTEx. Under matched conditions, we found around 80% of the eQTLs in one study can be replicated in the other. However, among all eQTLs identified in GenCord (GTEx), 584 (1045) showed statistically significant differences in effect sizes in GTEx (GenCord). We further investigated how using fetal eQTL data can facilitate the genetic association study of acute lymphoblastic leukemia. GenCord and GTEx identified the same genetic loci with statistical significance; however, the overall association pattern was only weakly correlated. Our paper demonstrates age-differential eQTLs and shows their potential influence on childhood leukemia research.