Fig. 3: Bidirectional Manhattan plots displaying Down syndrome (DS)-associated CpGs and differentially methylated regions (DMRs) genome-wide.
From: The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis
a Manhattan plot presenting the −log10(P) values of autosomal CpGs derived from the multiethnic epigenome-wide association study (EWAS) of DS. P values were calculated using linear regression testing the association of each CpG beta-value with DS, adjusting for sex, plate, the first ten ReFACToR principal components (PCs), and the first ten EPISTRUCTURE PCs. Points above zero correspond to CpGs that were hypermethylated in DS (N = 196) versus non-DS (N = 439) newborns, whereas points below zero correspond to hypomethylated CpGs in DS. The genomic inflation factor (λ) was 1.47. Dotted lines correspond to the threshold for epigenome-wide significance (P = 7.67 × 10−8) after Bonferroni correction for multiple testing. The strong association peaks at FLI1 on chromosome 11 and RUNX1 on chromosome 21 are highlighted. b Manhattan plot showing DMRs identified in the overall multiethnic analysis using DMRcate and comb-p. The –log10(P) values were derived from the Šidák-corrected P values from the more stringent method, comb-p, with the DS EWAS P values at each CpG as input. Points above zero correspond to DMRs with a mean Δβ-value above 0 (hypermethylated in DS), whereas points below zero correspond to hypomethylated DMRs in DS. The top two significant DMRs in RUNX1 and FLI1 are highlighted. We identified DMRs in several additional genes that regulate hematopoiesis and/or are known drivers of leukemogenesis, including at Hsa21 genes DYRK1A (DMR N = 3), ERG (N = 2), and ETS2 (N = 1), and at non-Hsa21 genes ETV6 (N = 3), BCR and KIT (both N = 2), and GATA2, TET1, TET2, FLT3, DNMT3A, KAT6B, KMT2C, PBX1, and RARA (all N = 1) (Supplementary Data 7).
