From GWAS to PheWAS: Scanning the EMR phenome for gene-disease associations

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DESCRIPTION (provided by applicant): Genomic medicine offers hope for improved diagnostic methods and for more effective, patient-specific therapies. Genome-wide associated studies (GWAS) elucidate genetic markers that improve understanding of risks and causes for many diseases, and may guide diagnosis and therapy on a patient-specific basis. This project will take another approach to identify gene-disease associations: perform "reverse GWAS," or phenome- wide association study (PheWAS), to determine which phenotypes are associated with a given genotype. The project is enabled by a large DNA biobank coupled to a de- identified copy of the electronic medical record. This project has four specific aims. First, the project will develop and validate a standardized approach to extract disease phenotypes from EMR records, integrating national standard terminologies of clinical disorders and descriptors relating to treatment and diagnosis of each disease to create a sharable knowledge base. The project will use natural language processing, structured data queries, and heuristic and machine learning methods to accurately identify patients with each disease and corresponding controls. The second aim is to perform PheWAS analyses using existing genotype data. To validate the method, the project will use PheWAS to "rediscover" SNPs with known disease associations. The project will also investigate statistical methods for large-scale multiple hypothesis testing to discover novel phenotype associations. The third aim is to apply the PheWAS algorithms in four other sites with EMR-linked DNA biobanks and compare results. In the fourth aim, the project will validate novel phenotype-genotype associations discovered through PheWAS with new genotyping in a previously untested population. The tools generated from this project will not only make PheWAS possible, but will also broadly enable clinical research and subsequent genetic studies.