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

Phenome-wide Association Studies (PheWASs) for Functional Variants

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Free PMC article

Phenome-wide Association Studies (PheWASs) for Functional Variants

Zhan Ye et al. Eur J Hum Genet. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Manhattan plots of unadjusted −log10 (P-values) for the 4841 ICD9 and V codes that define the phenome. Highlighted are association results for (a) multiple sclerosis (ICD9 340) for rs3135388, (b) other inflammatory spondylopathies (ICD9 720.8) for rs9501572, (c) pure hyperglyceridemia (ICD9 272.1) for rs328, (d) atrial fibrillation (ICD9 427.31 and 427.3) for rs2200733, and (e) age-related macular degeneration (AMD) (ICD9 362.50, 362.51, 362.52, and 362.5) for rs1061170.
Figure 2
Figure 2
Manhattan plots of unadjusted −log10 (P-values) for the nonsense variant rs2736911 in ARMS2. Highlighted is the ICD9 code for wet age-related macular degeneration (AMD) in the (a) discovery set, (b) validation set, and (c) meta-analysis.

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