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

IF 9.6 1区医学 Q1 NEUROSCIENCES Biological Psychiatry Pub Date : 2025-03-18 DOI:10.1016/j.biopsych.2025.03.006

Josephine Mollon, Laura M Schultz, Emma Em Knowles, Sebastien Jacquemont, David C Glahn, Laura Almasy

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Abstract

Background: There has been little examination of the stability and validity of polygenic risk scores (PRS) 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 aged 37-73 in the UK between 2006-2010. PRS were calculated for 408,853 white British individuals. PRS-CS, which uses SNP effect sizes under continuous shrinkage, was used to calculate three different PRS for major depressive disorder (MDD), alcohol use disorder (AUD), and type 2 diabetes (T2D), and two different PRS for schizophrenia (SCZ). PRS stability was measured using correlations between different PRS for the same disorder, and percentage of individuals consistently identified as high-risk (top 5% PRS). Sensitivity and specificity were used to measure PRS validity.

Results: Correlations between PRS ranged from low to high (SCZ: r=0.78; MDD: r=0.16-0.78; AUD: r=0.13-0.90; T2D r=0.29-0.77). Percentage of individuals consistently identified as high-risk (top 5% PRS) for schizophrenia with 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 9.5-47.0% for MDD, 8.3-63.5% for AUD, and 14.1-45.2% for T2D. Sensitivity of PRS 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 PRS (50.7-56.4%).

Conclusions: Limited stability and specificity of PRS highlight their lack of clinical utility in psychiatry.

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主要精神疾病多基因风险评分的低稳定性和特异性限制了其临床实用性。

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来源期刊

Biological Psychiatry 医学-精神病学

CiteScore

18.80

自引率

2.80%

发文量

1398

审稿时长

33 days

期刊介绍： Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.