Lost-of-function variants in the 1000 genomes data set and implications to GWAS

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DESCRIPTION (provided by applicant): The 1000 Genomes Project is an international research consortium whose aim is to produce a detailed map of human genetic variation to support disease studies with major sequencing effort. This project involves sequencing the genomes of at least a thousand people from around the world to facilitate the discovery and understanding of genetic variants such as single nucleotide polymorphisms and structural variants. The data generated from this project will help in the discovery of regions in the genome containing genetic variations associated with risk of human diseases as previously attempted by efforts such as the HapMap Project. However, there are significant challenges in the analysis, annotation, and applications of these data to guide the identifications of variants associated with diseases and various traits. In this application, we will focus on loss-of-function variants because they represent a major class of genetic variations that are potentially involved in complex traits, and we believe a comprehensive characterization of these variants and making the knowledge gained available to the general research community will facilitate the identifications of genes involved in complex traits. To accomplish this objective, we will develop a bioinformatics pipeline to identify loss-of-function variants from the 1000 genome data, associate them with other types of information accumulated in the literature and public databases, such as gene ontology, protein interactions, expression profiles, investigate the best approaches to attain the genotypes of these variants in population samples, and develop statistical methods to incorporate the annotation results to increase the statistical power to identify loss of function variants affecting complex traits. We will disseminate the methods and results to the public both through a stand-alone application focusing of loss of function variants as well as through collaboration with the UCSC Genome Browser team to add tracks on their browser to different types of information on these loss of function variants. We believe that this proposed project will generate very valuable resources to the scientific community that can significantly enhance our understanding of loss of function variants in human populations and use such knowledge to more effectively improve human health. RELEVANCE: The research proposal is developed to generate very valuable resources to the scientific community that can significantly enhance our understanding of loss of function variants in human populations and use such knowledge to more effectively improve human health.