Phenome-wide association studies (PheWASs) for functional variants.
Zhan Ye1, John Mayer1, Lynn Ivacic2
1Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
European Journal of Human Genetics : EJHG
|July 31, 2014
Summary
Phenome-wide association studies (PheWAS) can identify gene-disease links. Focusing on functional variants, like a nonsense variant in ARMS2, may improve discovery of associations, such as with age-related macular degeneration (AMD).
Area of Science:
- Genetics
- Human Disease Research
- Bioinformatics
Background:
- Genome-wide association studies (GWAS) identify genetic disease links but often struggle with functional interpretation.
- Phenome-wide association studies (PheWAS) offer a genotype-to-phenotype approach using electronic health records.
- Previous PheWAS primarily used GWAS-identified variants, limiting discovery due to weak effect sizes and functional ambiguity.
Purpose of the Study:
- To investigate the utility of focusing on functional variants in PheWAS.
- To identify novel gene-disease associations by analyzing presumed functional variants.
- To overcome limitations of traditional GWAS-based PheWAS.
Main Methods:
- Conducted a PheWAS on 105 presumed functional stop-gain and stop-loss variants.
- Genotyped 4235 Marshfield Clinic patients for initial analysis.
- Validated associations in an additional 10,640 Marshfield Clinic patients.
Main Results:
- Identified a significant association between a nonsense variant in ARMS2 (rs2736911) and age-related macular degeneration (AMD).
- Demonstrated pleiotropic effects for some functional variants.
- Confirmed the utility of functional variants in PheWAS.
Conclusions:
- Focusing PheWAS on functional variants is an effective strategy for discovering gene-disease associations.
- This approach enhances the translation of genetic discoveries into clinical understanding.
- Highlights the potential of ARMS2 functional variants in AMD etiology.
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