Chunk #27 — Polygenic Risk Scores: A Bridge Between Population Variation and Individual Differences — PRS Practicalities — Technical Considerations. — Improvements in Discovery GWAS:
In addition to increasing the sample size of discovery GWAS and using new tools to improve the utility of PRS available from current GWAS summary statistics, improving discovery GWAS phenotyping may also produce more reliable, applicable, and precise PRS. Indeed, relying on GWAS of psychiatric disorders may be problematic for refining nosology and mechanistic understanding because many, if not all, psychiatric disorders represent heterogeneous amalgamations of symptoms and their correlates. Such heterogeneity may dilute observed genetic effects or result in the identification of broad and generalized genetic associations that may not be applicable to more specific phenotypes. For example, many patients with MDD do not exhibit the cardinal symptom of anhedonia (Treadway and Zald, 2011). Thus, genetic associations with heterogeneous MDD not predicated on the presence of anhedonia, may not be informative for reward-related neural or behavioral phenotypes (Bogdan et al., 2013). The potential implications of GWAS phenotyping may be observed when contrasting two GWAS of depression. In the larger study, which contained 9,240 MDD cases and 9,519 controls, no genomewide significant loci were detected (Major Depressive Disorder Working Group
