title: Phenome-wide association studies (PheWASs) for functional variants.
abstract: 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.
authors: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors: Zhan
authors: Z
authors: Ye
authors: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors: John
authors: J
authors: Mayer
authors: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors: Lynn
authors: L
authors: Ivacic
authors: Parkland Center for Clinical Innovation, Parkland Health and Hospital System, Dallas, TX, USA.
authors: Zhiyi
authors: Z
authors: Zhou
authors: 1] Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA [2] Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors: Min
authors: M
authors: He
authors: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors: Steven J
authors: SJ
authors: Schrodi
authors: Computation and Informatics in Biology and Medicine, University of Wisconsin Madison, Madison, WI, USA.
authors: David
authors: D
authors: Page
authors: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors: Murray H
authors: MH
authors: Brilliant
authors: 1] Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA [2] Computation and Informatics in Biology and Medicine, University of Wisconsin Madison, Madison, WI, USA.
authors: Scott J
authors: SJ
authors: Hebbring
mesh_terms: D030541:Databases, Genetic; D057286:Electronic Health Records; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D015203:Reproducibility of Results
chemical_list: C514392:ARMS2 protein, human; D011506:Proteins