Acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) are poorly understood and under- studied diseases with high mortality rates. While few environmental risk factors have been identified in ALL, genetic susceptibility to pediatric ALL has been confirmed in recent genome wide association studies (GWAS). However, these studies were performed testing a limited number of common variants in pediatric patients, leaving unanswered questions about genetic susceptibility to ALL across the life span, as well as the role of common and rare variation. Unlike ALL, germ-line genetic variation studies focused on AML susceptibility have not been published. Our approach, study population and disease focus allow the data generated from the primary R01 (R01 HL102778-04) to be used in an innovative manner, leading to unique insights into the contribution of genetics to ALL and AML susceptibility. Our proposed research is expected to elucidate pathways for leukemia risk by agnostically interrogating both common and less common constitutional (inherited) genetic markers. We hypothesize that common and rare germ-line genetic variation significantly contributes to increased odds of ALL and AML. To test these hypotheses, we will use a case control study design leveraging existing data from our parent R01 study which produced high quality demographic, human leukocyte antigen (HLA) and genome-wide data on thousands of well-characterized ALL and AML patients (cases) treated with an allogeneic hematopoietic cell transplant (AlloHCT) and their unrelated healthy donors (controls). Our study population consists of both pediatric and adult ALL cases which allows us to gain greater understanding of age-associated genetic effects in ALL, e.g., do susceptibility variants in young children (<10 years) show the same association in older children and adults. This is particularly relevant due to the preliminary findings of changes in strength of genetic variants in ARID5B with ALL across age in published GWAS. In addition, our study population has a unique feature with the availability of high resolution HLA-typed cases (alloHCT recipients) and controls (matched unrelated alloHCT donors), which will allow innovative modeling, including matched pair analyses, to yield a greater understanding of the relationship of common and rare genetic variation, HLA type and disease. HLA have recently been implicated in pediatric ALL susceptibility and postulated for AML. By leveraging a large existing GWAS, the proposed aims will contribute to significant understanding of the common and rare genetic basis of ALL and AML risk, as well as age related genetic associations in ALL and AML. This knowledge could lead to significant future improvements in earlier detection, and perhaps prevention, of these deadly cancers.