Genome-Wide Association Study of Acute Lymphoblastic Leukemia in Hispanic/Latino Children Identifies a Putatively Novel Risk Locus at Chromosome 5q31.1

Introduction: Children of self-reported Hispanic/Latino ethnicity have the highest risk of acute lymphoblastic leukemia (ALL) compared with other racial/ethnic groups in the United States. Genome-wide association studies (GWAS) have identified several genetic risk loci for childhood ALL, including at ARID5B, GATA3, and IKZF1, in which the higher risk allele frequencies in Hispanic/Latino populations compared with European ancestry populations may contribute to the disparity in ALL risk. We performed the largest GWAS of childhood ALL in Hispanic/Latino individuals to identify additional risk loci that may be enriched in this population.

Methods: We included data from four studies, totaling 3,880 self-reported Hispanic/Latino childhood ALL cases and 12,439 controls for a meta-analysis GWAS: 1) 1,930 cases and 8,520 controls from the California Cancer Records Linkage Project (CCRLP; including additional controls from the Resource for Genetic Epidemiology Research on Aging); 2) 605 cases and 515 controls from the California Childhood Leukemia Study (CCLS); 3) 510 cases from the Texas ALL study and 2,285 controls from Hispanic Community Health Study/Study of Latinos (HCHS/SOL); and 4) 835 cases from a Children’s Oncology Group/St. Jude Children’s Hospital ALL study and 1,119 controls from the Multi-ethnic Study of Atherosclerosis (MESA). Using individual-level single nucleotide polymorphism (SNP) genotype data from each study, we performed consistent quality control filtering of samples and SNPs followed by genome-wide imputation with the TOPMed Imputation Server. Post-imputation, we excluded variants with minor allele frequency (MAF) <0.01, and those with poor imputation quality scores. GWAS for each study were conducted using PLINK 2.0, adjusting for sex and the first 20 principal components to account for population structure. A fixed-effect inverse-variance weighted meta-analysis was performed using METAL with a genome-wide significance threshold of P < 5x10^-8.

Results: Genome-wide significant association signals were identified at known ALL risk loci including ARID5B, IKZF1, CEBPE, GATA3, CDKN2A, BMI1, PIP4K2A, and ERG. In addition, we identified a putative novel risk locus at chromosome 5q31.1 with an association peak spanning the DNA repair gene RAD50 and interleukin genes IL4, IL5, and IL13. The top hit SNP rs75929455 (P = 6.37x10^-8, odds ratio [OR] = 1.31; 95%CI: 1.19-1.44) resides in the 3’ end of RAD50, which forms a complex with the ALL predisposition gene NBN. A nearby linked (R²=0.68) SNP rs181273766 (P = 1.37x10^-7, OR = 1.31; 95%CI: 1.19-1.45) resides in the promoter region of IL13, a cytokine involved in allergies, infection, and B-cell proliferation. An additional 11 SNPs in this locus had p-values < 5x10^-7, all showing consistent direction of effect across all four studies with no evidence of significant heterogeneity. This region includes multiple known GWAS associations for white blood cell counts and immune-related diseases. Of interest, SNP rs181273766 has MAF=0.049 in Hispanic/Latino populations in the Genome Aggregation Database (gnomAD), with the highest MAF=0.16 in Peruvians, but is ultra-rare in Europeans (MAF=0.0001) and rare in East Asian (MAF<0.003) and African (MAF<0.002) populations. Among Hispanics/Latinos in gnomAD partitioned by ancestry at this locus, the SNP MAF is 0.17 in the Amerindigenous ancestry group and 0.001 in the European group. Consistent with this risk allele being enriched in Amerindigenous ancestry, in our data each copy of local Amerindigenous haplotype was significantly associated with an ~10% increased odds of ALL (P = 0.01, OR = 1.10; 95%CI: 1.02-1.19).

Conclusions: We have identified a putative novel association locus for childhood ALL at chr5q31.1 that may be specific to Hispanic/Latino individuals and contribute to the increased ALL risk in this population. Replication in additional cohorts will be required to confirm this novel risk association, and functional analysis of variants in this region may reveal novel insights into ALL biology.