Phenome-wide association studies (PheWASs) for functional variants.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Ye, Z; Mayer, J; Ivacic, L; Zhou, Z; He, M; Schrodi, SJ; Page, D; Brilliant, MH; Hebbring, SJ

Published Date

  • April 2015

Published In

Volume / Issue

  • 23 / 4

Start / End Page

  • 523 - 529

PubMed ID

  • 25074467

Pubmed Central ID

  • 25074467

Electronic International Standard Serial Number (EISSN)

  • 1476-5438

Digital Object Identifier (DOI)

  • 10.1038/ejhg.2014.123


  • eng

Conference Location

  • England