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

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PROJECT SUMMARY/ABSTRACT The overarching goal 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 investigate the impact of genetic ancestry on risk of ALL in Latino populations. Over the past few decades, incidence of ALL has increased on both a global and national scale. While this increase is present in all populations, the rates of incidence, poorer prognosis, and complications are substantially higher in Latino children than their non-Latino counterparts. Previous literature has identified an immunological, genetic, and evolutionary etiology to ALL risk. Specifically, Native American ancestry, due to the evolutionary history of Latin America, is associated with increased risk of ALL. While the differences in risk among Latinos is evident, there remains a gap in the literature in development and application of computational methods to study the genetic risk of complex diseases in diverse and admixed populations. Given that approximately 80% of study subjects in published Genome Wide Association Studies are of European descent, our understanding of the genetics of ALL may have limited external validity and generalizability. This proposed project seeks to tandemly address the etiology of elevated ALL risk in Latinos 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 increasing copies of Native American ancestry harboring population-specific risk alleles will be positively associated with risk of ALL, Ms. Langie will implement a form of GWAS 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 Native American 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).