Phenome-wide association studies (PheWASs) for functional variants

Eur J Hum Genet. 2015 Apr;23(4):523-9. doi: 10.1038/ejhg.2014.123. Epub 2014 Jul 30.


The genome-wide association study (GWAS) is a powerful approach for studying the genetic complexities of human disease. Unfortunately, GWASs often fail to identify clinically significant associations and describing function can be a challenge. GWAS is a phenotype-to-genotype approach. It is now possible to conduct a converse genotype-to-phenotype approach using extensive electronic medical records to define a phenome. This approach associates a single genetic variant with many phenotypes across the phenome and is called a phenome-wide association study (PheWAS). The majority of PheWASs conducted have focused on variants identified previously by GWASs. This approach has been efficient for rediscovering gene-disease associations while also identifying pleiotropic effects for some single-nucleotide polymorphisms (SNPs). However, the use of SNPs identified by GWAS in a PheWAS is limited by the inherent properties of the GWAS SNPs, including weak effect sizes and difficulty when translating discoveries to function. To address these challenges, we conducted a PheWAS on 105 presumed functional stop-gain and stop-loss variants genotyped on 4235 Marshfield Clinic patients. Associations were validated on an additional 10 640 Marshfield Clinic patients. PheWAS results indicate that a nonsense variant in ARMS2 (rs2736911) is associated with age-related macular degeneration (AMD). These results demonstrate that focusing on functional variants may be an effective approach when conducting a PheWAS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Databases, Genetic
  • Electronic Health Records
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods*
  • Genotype
  • Humans
  • Macular Degeneration / genetics
  • Phenotype*
  • Polymorphism, Single Nucleotide*
  • Proteins / genetics
  • Reproducibility of Results


  • ARMS2 protein, human
  • Proteins