Fig. 6 |. Noncoding germline SVs impacting TAD boundaries in disease-relevant tissues increase risk for neuroblastoma.
(A) We performed a CWAS for rare, noncoding SVs in neuroblastoma cases vs. controls, finding that singleton germline SVs overlapping adrenal gland-derived TAD boundaries were significantly enriched in cases after correcting for the estimated number of effective CWAS tests (“Bonferroni”). (B) No noncoding SV categories reached the threshold of Bonferroni significance for enrichment in Ewing sarcoma cases relative to controls. (C) Quantile-quantile plots for all noncoding CWAS categories for neuroblastoma (top) and Ewing sarcoma (bottom) demonstrated good calibration of CWAS test statistics. Dashed horizontal line corresponds to Bonferroni significance. (D) We observed a significantly stronger effect size for noncoding singleton SVs intersecting TAD boundaries defined in the putative tissue-of-origin (adrenal gland) relative to all noncoding singletons in neuroblastoma (P=3.6×10−4, Welch’s t-test), whereas this difference was not seen in Ewing sarcoma (P=0.42), consistent with the lack of a TAD-related association in the Ewing sarcoma CWAS. (E) The enrichment in neuroblastoma cases for singleton germline SVs intersecting TAD boundaries was significant in the St. Jude and GMKF cohorts when analyzed separately. (F) Effect sizes for singleton SVs intersecting TAD boundaries in neuroblastoma increased monotonically when subsetting to deletions in proximity to genes expressed in adrenal tissue.