Admixture-driven discovery of disease-associated genetic variants not found in Europeans

DESCRIPTION provided by applicant Genetic studies have been conducted predominantly in cohorts of individuals of European ancestry By there were approximately ten times as many published genome wide association studies GWAS in people of European ancestry than studies in people of all other ancestries combined This research disparity has led to an uneven understanding in the genetic basis underlying disease in Europeans and non Europeans andMeandapos s web based large scale research model is ideal for scaling genetics research within non European populations and bring more parity in genetic research With our previous SBIR grant R HG we expanded andMeandapos s tools to mine the genetic and phenotypic information in the database largely through improved survey data collection as well as better management and computational tools This proposal will extend andMeandapos s infrastructure for association studies to leverage the variation found in admixed individuals individuals with ancestry from multiple continents We will develop a pipeline for large scale computationally efficient admixture mapping that allows us to interrogate the variation in admixed genomes Admixture mapping looks for regions of the genome that have an enrichment of one ancestral background in individuals with a disease indicative of the presence of risk variants that differ i frequency among the ancestral populations andMeandapos s genotype phenotype database derived from over research consented customers includes data from over Latinos and African Americans In our proposal we aim to harness genetic admixture to drive the discovery of disease variants found in non Europeans especially variants of African and Native American origin found in the admixed genomes of African Americans and Latinos Unlike previous admixture mapping studies which typically relied on small sets of ancestry informative markers we will leverage andMeandapos s fine scale local ancestry estimates and growing genotype phenotype database for admixture mapping in thousands of individuals across dozens of phenotypes We will implement an admixture mapping pipeline that leverages our existing infrastructure for fine scale local ancestry inference and validate the pipeline through replicatin of a previous hit Aim We will apply our pipeline to several diseases that have been either previously targeted by admixture mapping studies or have been identified by the CDC as contributing to growing health disparities among groups which will require determining which combination of cohorts and ancestries will give rise to greatest power in finding genetic associations Aim Lastly we follow up our top novel target to both validate findings and fine map Aim This proposal will expand andMeandapos s research pipeline to include admixture mapping and improve the understanding of global genetic variation underlying diseases and traits Key commercial outcomes of the research are novel genetic targets for internal and external therapeutic development The long term aim is to improve understanding of disease in minority populations which we hope may eventually lead to improved treatments of disease in these historically medically understudied groups

PUBLIC HEALTH RELEVANCE Genome wide association studies have yielded many discoveries of genes associated with disease but largely in European populations This proposal aims to discover new associations of genetic variants from globally diverse backgrounds by developing methods that take advantage of information in genetically admixed andMe research participants This study will enable andMe to improve the knowledge of disease variants found in non Europeans especially variants of African and Native American origin found today in African Americans and Latinos