Abstract
Myeloid leukemia of Down syndrome (DS) is preceded by a transient neonatal preleukemia driven by somatic mutations in the chromosome X gene GATA1, resulting in a shorter protein isoform (GATA1s). GATA1s mutations occur at high frequency in DS, but beyond trisomy 21, risk factors for this preleukemia are unknown. We investigated whether germline genetic variation influences development of GATA1s mutations in DS. Whole-genome sequencing was performed on 434 children with DS from the Oxford DS Cohort Study previously screened for GATA1s mutations. After quality control, association tests were conducted separately for disomic autosomes, trisomic chromosome 21, and chromosome X. Regression tests were performed for mutation variant allele frequency or the binary trait (103 GATA1s-positive cases, 326 controls), adjusting for sex and ancestry-related principal components. Genetic ancestry of each participant was inferred and tested for association with GATA1s mutations. We identified 3 genome-wide significant (P < 5 × 10-8) loci associated with GATA1s mutations. However, these may be false positives because few linked variants showed evidence of association at each locus. No significant associations were detected on chromosome 21 or the GATA1 region on chromosome X. Increasing proportions of South Asian genetic ancestry were associated with an increased risk of GATA1s mutations, with each 10% increase in ancestry associated with a 1.11-fold higher risk of developing GATA1s mutations (P = .031). Our genetic epidemiology study of somatic GATA1s mutations in DS did not identify strong germ line genetic effects. The association with genetic ancestry may relate to unmeasured genetic or nongenetic effects, such as fetal exposures, and warrants further investigation.