Low Stability and Specificity of Polygenic Risk Scores for Major Psychiatric Disorders Limit Their Clinical Utility

Abstract

Background

There has been little examination of the stability and validity of polygenic risk scores (PRSs), i.e., whether individuals identified as high risk for a disorder with one PRS are identified as high risk with another PRS and whether high-risk individuals have the disorder.

Methods

The UK Biobank recruited 502,534 individuals ages 37 to 73 years in the United Kingdom between 2006 and 2010. PRSs were calculated for 408,853 White British individuals. PRS continuous shrinkage (CS), which uses single nucleotide polymorphism effect sizes under CS, was used to calculate 3 different PRSs for major depressive disorder (MDD), alcohol use disorder (AUD), and type 2 diabetes (T2D) and 2 different PRSs for schizophrenia (SCZ). PRS stability was measured using correlations between different PRSs for the same disorder and the percentage of individuals consistently identified as high risk (top 5% PRS). Sensitivity and specificity were used to measure PRS validity.

Results

Correlations between PRSs ranged from low to high (SCZ: r = 0.78; MDD: rs = 0.16–0.78; AUD: rs = 0.13–0.90; T2D rs = 0.29–0.77). The percentage of individuals consistently identified as high risk (top 5% PRS) for SCZ with a different SCZ PRS was 47.7%, i.e., less than half of individuals identified as high risk with one PRS were identified as high risk with another PRS. Percentages of individuals consistently identified as high risk were 9.5% to 47.0% for MDD, 8.3% to 63.5% for AUD, and 14.1% to 45.2% for T2D. PRS sensitivity was moderate for MDD (66.1%–74.4%) and AUD (72.3%–74.2%), moderate/good for T2D (77.3%–96.3%), and good for SCZ (90.2%–93.3%). Specificity was low for all PRSs (50.7%–56.4%).

Conclusions

Limited stability and specificity of PRSs highlight their current lack of clinical utility in psychiatry.