Chunk #25 — Limitations and misunderstandings of clinical, translational, and research applications of PRS — Uneven common variant risk contributions across the phenotypic spectrum
For many traits, risk is additively conferred by variants across the frequency spectrum, ranging from de novo (i.e., newly arising) to common, only the latter of which is captured by PRS. While rare variants can have larger effects than common variants (Figure 2E), most heritable variation in a population is explained by the latter (Figure 2D) (69–75). Some autism spectrum disorders (ASD) and intellectual disability (ID) patients have high polygenic risk and large effect rare variants contributing to their case status (69), but relatively few have solely pathogenic de novo causes (73). These variants can contribute more to syndromic features (e.g. for ASD and ID); for example, developmental disability patients with severe ID (76) or craniofacial dysmorphia (71) are more likely to carry a strong acting de novo variant than individuals with mild developmental delays and more typical physical features.
