Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese

Abstract

Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0-19 years) previously enrolled onto a Tokyo Children's Cancer Study Group trial were collected during 2013-2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10^-17) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10^-4) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10^-6). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.

Figure 1

Regional plot of results of the association between SNPs in (a) ARID5B, (b) PIP4K2A, and (c) IKZF1 and risk of childhood B-cell ALL. Multiple logistic regression was performed assuming a log-additive genetic model and adjusting for 10 principal components eigenvectors. The −log10 (p-value) for each SNP are plotted against their chromosomal position. The purple diamond (♦) indicates the strongest associated SNP in the region and the colors of the dots (•) represent the degree of linkage disequilibrium (based on r²) in relation to that index SNP in Japanese. Recombination rates (cM/Mb) overlay the plots. Coordinates are based on human genome assembly GRCh37 build.