Polygenic risk scores in psychiatry: Will they be useful for clinicians?

Abstract

Major psychiatric disorders are heritable but they are genetically complex. This means that, with certain exceptions, single gene markers will not be helpful for diagnosis. However, we are learning more about the large number of gene variants that, in combination, are associated with risk for disorders such as schizophrenia, bipolar disorder, and other psychiatric conditions. The presence of those risk variants may now be combined into a polygenic risk score (PRS). Such a score provides a quantitative index of the genomic burden of risk variants in an individual, which relates to the likelihood that a person has a particular disorder. Currently, such scores are quite useful in research, and they are telling us much about the relationships between different disorders and other indices of brain function. In the future, as the datasets supporting the development of such scores become larger and more diverse and as methodological developments improve predictive capacity, we expect that PRS will have substantial clinical utility in the assessment of risk for disease, subtypes of disease, and even treatment response. Here, we provide an overview of PRS in general terms (including a glossary suitable for informed non-geneticists) and discuss the use of PRS in psychiatry, including their limitations and cautions for interpretation, as well as their applications now and in the future.

Modulation of Stem Cells as Therapeutics for Severe Mental Disorders and Cognitive Impairments

“…Among them, schizophrenia and BD affect 2-4% of the world population. Current medications have not shown significant improvement in these diseases (1,2). Researchers have sought to identify a clinically relevant brain pathology of schizophrenia or bipolar disorder behind the persistent psychosis condition, which still appears to be unknown (3).…”

Psychosocial implications of living with familial risk of a psychiatric disorder and attitudes to psychiatric genetic testing: A systematic review of the literature

“…Currently genetic testing for psychiatric disorders is not widely available clinically (Fullerton & Nurnberger, 2019), given the nascent state of research, and the fact that more data are needed to demonstrate the clinical utility of genetic testing. However, large ongoing research projects are contributing to the effort to develop diagnostic and predictive genetic tests that may influence routine clinical practice in psychiatry (Demkow & Wolańczyk, 2017).…”

“…The use of PRS is currently limited to research contexts, where they are used for various purposes including predicting treatment outcomes (Frank et al, 2014; Santoro et al, 2018; Ward et al, 2018) and assessing genetic overlap between disorders (St Pourcain et al, 2018). It has also been argued that in the future, as the datasets supporting the development of such scores become larger, PRS may have clinical utility to assess risk for disease, subtypes of disease, and even treatment response (Fullerton & Nurnberger, 2019). PRS may also be able to aid differential diagnosis (Palk et al, 2019), given that PRS have recently been used to identify both shared genetic components and genetic differences between schizophrenia and bipolar disorder (Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2018).…”

Polygenic risk scores and their potential clinical use in psychiatry: are we there yet?

“…All in all, the consensus is that PRSs are still not very informative at the individual level, and therefore are premature for any clinical use at this moment. 4 The ability to calculate the genetic burden for psychiatric disorders using PRSs offers many important and clinically significant possibilities. However, it is clear that, at this point, PRSs alone are insufficient to fully capture and explain the genetic risk for these complex and multifactorial conditions.…”

“…In addition, an important limitation that hinders the broader use of PRSs in the clinical setting is the lack of ethnic diversity of the GWAS performed for psychiatric disorders to date (the largest PGC studies are overwhelmingly dominated by Caucasian subjects of European descent); however, PRSs are known to be highly sensitive to ethnic background. 4 Finally, PRSs may not have high specificities due to the known pleiotropic relationships between psychiatric disorders, in addition to the fact that they do not take environmental effects into account. All in all, the consensus is that PRSs are still not very informative at the individual level, and therefore are premature for any clinical use at this moment.…”