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Review
. 2014 Feb;141(2):157-65.
doi: 10.1111/imm.12195.

The challenges, advantages and future of phenome-wide association studies

Affiliations
Review

The challenges, advantages and future of phenome-wide association studies

Scott J Hebbring. Immunology. 2014 Feb.

Abstract

Over the last decade, significant technological breakthroughs have revolutionized human genomic research in the form of genome-wide association studies (GWASs). GWASs have identified thousands of statistically significant genetic variants associated with hundreds of human conditions including many with immunological aetiologies (e.g. multiple sclerosis, ankylosing spondylitis and rheumatoid arthritis). Unfortunately, most GWASs fail to identify clinically significant associations. Identifying biologically significant variants by GWAS also presents a challenge. The GWAS is a phenotype-to-genotype approach. As a complementary/alternative approach to the GWAS, investigators have begun to exploit extensive electronic medical record systems to conduct a genotype-to-phenotype approach when studying human disease - specifically, the phenome-wide association study (PheWAS). Although the PheWAS approach is in its infancy, this method has already demonstrated its capacity to rediscover important genetic associations related to immunological diseases/conditions. Furthermore, PheWAS has the advantage of identifying genetic variants with pleiotropic properties. This is particularly relevant for HLA variants. For example, PheWAS results have demonstrated that the HLA-DRB1 variant associated with multiple sclerosis may also be associated with erythematous conditions including rosacea. Likewise, PheWAS has demonstrated that the HLA-B genotype is not only associated with spondylopathies, uveitis, and variability in platelet count, but may also play an important role in other conditions, such as mastoiditis. This review will discuss and compare general PheWAS methodologies, describe both the challenges and advantages of the PheWAS, and provide insight into the potential directions in which PheWAS may lead.

Keywords: electronic medical record; genome-wide association study; phenome-wide association study.

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Figures

Figure 1
Figure 1
Representative results from (a) a genome-wide association study (GWAS) and (b) a phenome-wide association study (PheWAS). (a) Illustration of the phenotype-to-genotype strategy used by GWAS along with a representative GWAS depicted in the Manhattan plot graphing –log10(P-values) across the genome. (b) Illustration of the genotype-to-phenotype strategy used by PheWAS including a representative PheWAS for single nucleotide polymorphism (SNP) rs1061170, a SNP known to be associated with age-related macular degeneration (AMD). The AMD ICD9 codes are highlighted on the PheWAS Manhattan plot.
Figure 2
Figure 2
International Classification of Disease version 9 (ICD9) spectrum used to define the phenome in phenome-wide association studies (PheWASs). Underlined are ICD9 codes represented at varying levels of phenotypic resolution including rheumatoid arthritis (RA) and other inflammatory polyarthropathies (ICD9 714), juvenile chronic polyarthritis (ICD9 714.3), and monarticular juvenile RA (ICD9 714.3).

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