Phenotypic Annotation: Using Polygenic Scores to Translate Discoveries From Genome-Wide Association Studies From the Top Down

Abstract

Genome-wide association studies (GWASs) have identified specific genetic variants associated with complex human traits and behaviors, such as educational attainment, mental disorders, and personality. However, small effect sizes for individual variants, uncertainty regarding the biological function of discovered genotypes, and potential “outside-the-skin” environmental mechanisms leave a translational gulf between GWAS results and scientific understanding that will improve human health and well-being. We propose a set of social, behavioral, and brain-science research activities that map discovered genotypes to neural, developmental, and social mechanisms and call this research program phenotypic annotation. Phenotypic annotation involves (a) elaborating the nomological network surrounding discovered genotypes, (b) shifting focus from individual genes to whole genomes, and (c) testing how discovered genotypes affect life-span development. Phenotypic-annotation research is already advancing the understanding of GWAS discoveries for educational attainment and schizophrenia. We review examples and discuss methodological considerations for psychologists taking up the phenotypic-annotation approach.