Embracing Complex Associations in Common Traits: Critical Considerations for Precision Medicine

Genome-wide association studies (GWAS) have identified numerous loci associated with human phenotypes. This approach, however, does not consider the richly diverse and complex environment with which humans interact throughout the life course, nor does it allow for interrelationships between genetic loci and across traits. As we move toward making precision medicine a reality, whereby we make predictions about disease risk based on genomic profiles, we need to identify improved predictive models of the relationship between genome and phenome. Methods that embrace pleiotropy (the effect of one locus on more than one trait), and gene–environment (G × E) and gene–gene (G × G) interactions, will further unveil the impact of alterations in biological pathways and identify genes that are only involved with disease in the context of the environment. This valuable information can be used to assess personal risk and choose the most appropriate medical interventions based on the genotype and environment of an individual, the whole premise of precision medicine.

TrendsGWAS have identified some of the genetic elements to explain some heritability of complex traits.GWAS are limited for precision medicine and predicting individual risk because they fail to embrace the complexity of biology.Focusing on pleiotropy, G × E interactions, and G × G interactions will enhance our ability to develop predictive models of the disease risk of an individual.