Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data

Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for a human disease; many of these associations require further study to replicate the results. Here we report the first c large-scale application of the phenome-wide association "study (PheWAS) paradigm within electronic medical records E (EMRs), an unbiased approach to replication and discovery. v that interrogates relationships between targeted genotypes 1s and multiple phenotypes. We scanned for associations z between 3,144 single-nucleotide polymorphisms (previously N implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 x 10(-6) (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.