Exploring the Impact of Genetic Ancestry on Acute Lymphoblastic Leukemia Risk in Latino Populations

The objective of this proposal is to employ and refine state-of-the-art gene discovery methods to uncover the genetic etiology of Acute Lymphoblastic Leukemia (ALL) risk and to leverage genetic admixture to identify new risk loci relevant to all human populations. Over the past few decades, incidence of ALL has increased on both a global and national scale. While strides in treatment of ALL, especially in children, have been made, the cure rate for children with high-risk subtypes and adults remains staggeringly low. Consequently, investigations into the etiology of the disease, with the overall aim of identifying new risk factors and designing new intervention and prevention strategies, is of clear importance. Previous literature has suggested an immunological and genetic etiology to ALL risk, with exposures such as early childhood infections and risk alleles at known lymphocyte development genes modulating risk. Further, genetic epidemiological studies have suggested that different genetic backgrounds may harbor genetic alleles that contribute to risks in individuals from the Americas. Our study thus presents a unique opportunity to use the historical admixture for ancestry-aware gene- and fine- mapping strategies, with the goal of uncovering genetic loci associated with the disease across populations. This proposed project seeks to tandemly elucidate the etiology of elevated ALL risk across different populations and add to the tools for genetic studies in admixed populations. Using over 3000 cases and 9000 controls from large population-based case-control and clinical trial studies, Ms. Langie will implement and develop gene discovery methods tailored to admixed populations to identify novel risk loci and causal genes associated with ALL. Given the overarching hypothesis that genetic ancestry from Americas may harbor population-enriched risk alleles associated with risk of ALL, Ms. Langie will implement a form of association testing that includes estimated local ancestry in the model and produces ancestry-specific effect sizes (Aim 1A). Furthermore, she will conduct admixture mapping and specifically test for the effect of genetic ancestry in ALL risk both locally and across the genome (Aim 1B). She will then perform multi-ethnic fine-mapping and gene-prioritization analysis at known and novel (discovered from Aim1) risk ALL loci to nominate plausible biological candidates for downstream functional and pharmacological investigations (Aim 2). Finally, she will develop a new method in admixture mapping that combines different study designs of admixture mapping studies to improve upon both the power and robustness of current designs (Aim 3).