Chunk #26 — Limitations and misunderstandings of clinical, translational, and research applications of PRS — Uneven common variant risk contributions across the phenotypic spectrum
Individuals with phenotypic extremes may be more likely to have average PRS than expected given the individuals’ deviation from the mean. This asymmetric observation about the imbalanced environmental or rare genetic contribution in phenotypic outliers is perhaps best illustrated by height, a continuous phenotype. We demonstrate this phenomenon by computing PRS for height in the UK Biobank using summary statistics from the GIANT consortium and comparing observed versus expected scores along the height distribution (77). Extremely short individuals are more likely to have monogenic or environmental factors contributing to their height than others, as demonstrated by less predictive polygenic scores (78) (Figure 4). As an analogy for this phenomenon in psychiatric disorders, very large contributing environmental effects, such as syphilis or toxic exposure to metals, potentially render polygenic risk irrelevant.
