Family‐based exome‐wide assessment of maternal genetic effects on susceptibility to childhood B‐cell acute lymphoblastic leukemia in hispanics

Abstract

Background Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) than other ethnic groups, but the genetic basis for racial disparities remain incompletely understood. Genome-wide association studies (GWAS) of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of maternal genotype on offspring phenotype development) may also play a role in ALL susceptibility. Methods We conducted a family-based exome-wide association study (EXWAS) of maternal genetic effects among Hispanics with childhood B-cell ALL (B-ALL) using the Illumina Human Exome BeadChip. We used a discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families. Results Three maternal SNPs approached our threshold for significance, after correction for multiple testing (P<1.0×10−6): MTL5 rs12365708 (RR=2.62, 95% CI=1.61-4.27, P=1.8×10−5); ALKBH1 rs6494 (RR=3.77, 95% CI=1.84-7.74, P=3.7×10−5); NEUROG3 rs4536103 (RR=1.75, 95% CI=1.30-2.37, P=1.2×10−4). While effect sizes were similar, these SNPs were not nominally significant in our replication cohort. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not statistically significant after correction for multiple comparisons (rs12365708: pooled RR=2.27, 95% CI=1.48-3.50, P=1.99×10−4; rs6494: pooled RR=2.31, 95% CI=1.38-3.85, P=0.001; rs4536103: pooled RR=1.67, 95% CI=1.29-2.16, P=9.23×10−5). Conclusions In the first family-based EXWAS to investigate maternal genotype effects associated with childhood ALL, our results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, we identified three maternal SNPs that may play a modest role in susceptibility.

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

“…This population has been described previously (25,26). Briefly, all individuals were genotyped using the Illumina Infinium HumanExome Bead Chip.…”

“…All patient data described here has been previously analyzed and published (14,15,25,26). In this study, we analyze summary statistics from these previous publications, with one exception: for the replication dataset (14), we obtained genotype data from dbGAP (Project ID 6249, PI Ramachandran) to calculate empirical LD for PEGASUS.…”

“…In this study, we analyze summary statistics from these previous publications, with one exception: for the replication dataset (14), we obtained genotype data from dbGAP (Project ID 6249, PI Ramachandran) to calculate empirical LD for PEGASUS. Please see Xu et al (15), Xu et al (14) and Archer et al (25) for details about institutional review of these studies and written informed consent.…”

“…We use genotype data from the multi-ethnic GWA study (14) to calculate empirical LD for PEGASUS analysis. We use LD information empirically calculated from the trios for the trio analysis-based gene-level test (25,26). …”

“…To identify genes and gene subnetworks influencing genetic predisposition for ALL, we analyzed two datasets of p -values from previously published case-control ALL GWA studies (14,15) and p -values from an ALL case-parent trio study (25,26). We used the gene-level association method PEGASUS (20) to identify novel candidate genes associated with ALL.…”