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

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

Author information

1
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
2
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
3
Parkland Center for Clinical Innovation, Parkland Health and Hospital System, Dallas, TX, USA.
4
1] Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA [2] Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
5
Computation and Informatics in Biology and Medicine, University of Wisconsin Madison, Madison, WI, USA.
6
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.

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.

PMID:
25074467
PMCID:
PMC4666492
DOI:
10.1038/ejhg.2014.123
[Indexed for MEDLINE]
Free PMC Article
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