Polygenic Risk Scores in Clinical Psychology: Bridging Genomic Risk to Individual Differences

Abstract

Genomewide association studies (GWASs) across psychiatric phenotypes have shown that common genetic variants generally confer risk with small effect sizes (odds ratio < 1.1) that additively contribute to polygenic risk. Summary statistics derived from large discovery GWASs can be used to generate polygenic risk scores (PRS) in independent, target data sets to examine correlates of polygenic disorder liability (e.g., does genetic liability to schizophrenia predict cognition?). The intuitive appeal and generalizability of PRS have led to their widespread use and new insights into mechanisms of polygenic liability. However, when currently applied across traits they account for small amounts of variance (<3%), are relatively uninformative for clinical treatment, and, in isolation, provide no insight into molecular mechanisms. Larger GWASs are needed to increase the precision of PRS, and novel approaches integrating various data sources (e.g., multitrait analysis of GWASs) may improve the utility of current PRS.

Keywords: GWAS; PRS; candidate; polygenic; psychopathology; schizophrenia.

Figure 1.. Practicalities of PRS computation.

Here, we exemplify using statistics from the most recent Psychiatric Genetics Consortium GWAS of schizophrenia (Schizophrenia Working Group, 2014) in which a discovery GWAS of 34,241 schizophrenia cases and 45,604 controls (initial discovery not including replication due to shared summary statistics). The effect allele and effect size for each SNP from the discovery GWAS is applied to each individual in a target dataset to create a unique person-specific polygenic risk score. We illustrate the approach using 4 SNPs. Summary statistics may be obtained here: https://www.med.unc.edu/pgc/results-and-downloads

Figure 2.. Schizophrenia PRS Effect Sizes Across 6 domains.

Plotted here is the range of the maximal percentage of variance explained by PGC SCZ2 PRS (Schizophrenia Working Group of the Psychiatric Genomics, 2014) in each study. Studies using other summary statistics are not included. Notably, as these are the maximal amount of variance explained and many studies reporting null effects did not report effect sizes, these estimates should be viewed as optimistic. The percentage of variance explained by Schizophrenia PRS in related traits ranges from 0.001 to 40% with 0.5–1.0% being most common. All = all identified Schizophrenia PRS studies. Course of illness = studies assessing course of illness. Psychiatric disorders and traits = studies evaluating other psychaitic disorders (e.g., bipolar disorder) or traits (e.g., neuroticism). Cognition = cognitive phenotypes (e.g., working memory). Brain-related = imaging phenotypes (e.g., cortical thickness), Health and immune function = immune (CRP levels) and reported health (e.g., physical health). Other = various other phenotypes related to schizophrenia (e.g., urbanicity). Individual studies contributing to this are summarized and * in Tables 1–6.