Figure 3: Multi-ethnic and functional analysis suggesting rs662463 is the causative BCP-ALL SNP tagged by the rs77728904-defined locus.
(a) eQTL analysis from GTEx22 in whole blood showing the association of CDKN2B expression with rs77728904 and rs662463 genotypes. For both SNPs, the minor allele is the risk allele. Each grey circle represents an individual. Each box plot shows the median rank normalized gene expression (black horizontal line), the first through third quartiles (purple box) and 1.5 × the interquartile range (whiskers). (b) Motifs derived from ChIP data showing the effect of rs662463 on CEBPB binding. The genomic sequence (Ref) surrounding rs662463 is shown below the CEBPB-binding site motif logo for K562 cells from Factorbook27, with the reference protective G-allele boxed and the risk A-allele in red. The CEBPB motif logo represents the position weight matrix (PWM) for each base. The PWM LOD scores calculated by HaploReg24 from TRANSFAC28 for two CEBPB-binding motifs (‘Tr1’ or TRANSFAC accession M00912 and ‘Tr2’ or TRANSFAC accession M00109) including either the protective or the risk allele of rs662463 demonstrate that the risk allele disrupts CEBPB binding. (c) RNA-seq analysis in European ancestry LCLs29, suggesting that the rs662463 genotype influences the correlation between CDKN2B and CEBPB expression, and that the rs662463 risk allele is associated with lower CDKN2B expression. Shown are the best-fit lines overall (black line), for LCLs homozygous for the protective allele (blue line) and for LCLs with at least one copy (one copy: green circles and two copies: red circles) of the risk allele (green line). (d) RNA-seq analysis in whole blood from an independent set of European ancestry individuals23, demonstrating that the rs662463 genotype significantly influences the correlation between CDKN2B and CEBPB expression. The rs662463 risk allele attenuates this correlation and is associated with lower CDKN2B expression. Shown are the best-fit lines overall (black line), for individuals homozygous for the protective allele (blue line) and for individuals with at least one copy (one copy: green circles and two copies: red circles) of the risk allele (green line).
