Chunk #29 — Polygenic Risk Scores: A Bridge Between Population Variation and Individual Differences — PRS Practicalities — Technical Considerations. — Improvements in Discovery GWAS:
2016). Further, other evidence suggests that traditionally conceptualized intermediate phenotypes (e.g., brain volume), may not be associated with larger effects related to common genetic variation suggesting potential limitations to “deeper” phenotyping (Franke et al., 2016). Going forward it will be important to not only have large studies, but also studies with deep phenotyping so that both heterogenous and more precise phenotypes could be leveraged and their predictive utility for cross-trait association contrasted. Indeed, the genetic architecture of a disorder may be partially or even fully distinct from the genetic architecture underlying related pathophysiology, its response to current treatment (see also Treatment Relevance), or its interplay with the environment (see also Other Applications). Lastly, for some disorders, which require exposure (e.g., substance use disorders, PTSD), it may be important to restrict controls of discovery GWAS to exposed individuals who have not been diagnosed with the disorder to identify sources of disorder liability. Such an approach was recently successful when considering opioid dependence when contrasting with opioid-exposed controls who did not progress to daily injection (Nelson et al., 2016).
