Multi-Phenotype Association Decomposition: Unraveling Complex Gene-Phenotype Relationships

Various patterns of multi-phenotype associations (MPAs) exist in the results of Genome Wide Association Studies (GWAS) involving different topologies of single nucleotide polymorphism (SNP)-phenotype associations. These can provide interesting information about the different impacts of a gene on closely related phenotypes or disparate phenotypes (pleiotropy).

Unraveling the complex genetic patterns underlying complex phenotypes has previously been challenging. While individual Genome-Wide Association Studies (GWAS) can provide insight into the genetic underpinnings of measured phenotypes, they typically involved associations of genetic variants with only one or a few phenotypes. The field of phenomics involves the collection of high-dimensional phenotype data of an organism, with the aim of capturing the overall, comprehensive phenotype (the “Phenome”) of the organism (Houle et al., 2010). Association studies involving many measured phenotypes, for example, Phenome-Wide Association Studies (PheWAS) present many advantages, in that they allow for the complex interconnected networks between phenotypes and their genetic underpinnings to be elucidated, and also allow for the detection of pleiotropy (Pendergrass et al., 2011, 2013, 2015; Hall et al., 2014).

Pleiotropy is the phenomenon in which a gene affects multiple phenotypes (Tyler et al., 2009). One can also have a locus-centric view of pleiotropy involving a single SNP affecting multiple phenotypes (Solovieff et al., 2013). While pleiotropy used to be considered an exception to the rules of Mendelian genetics, it has since been proposed to be a common, central property inherent to biological systems (Tyler et al., 2009).