Potential use of clinical polygenic risk scores in psychiatry – ethical implications and communicating high polygenic risk

Abstract

Psychiatric disorders present distinct clinical challenges which are partly attributable to their multifactorial aetiology and the absence of laboratory tests that can be used to confirm diagnosis or predict risk. Psychiatric disorders are highly heritable, but also polygenic, with genetic risk conferred by interactions between thousands of variants of small effect that can be summarized in a polygenic risk score. We discuss four areas in which the use of polygenic risk scores in research and clinical contexts could have ethical implications , with a particular focus on potential challenges that could arise with the feedback and interpretation of high polygenic risk for a psychiatric disorder . While there would be extensive overlap with the challenges of feeding back genetic findings in general, the potential clinical use of polygenic risk scoring warrants discussion in its own right, given the recency of this possibility. To this end, we discuss how lay interpretations of risk and genetic information could intersect. Consideration of these factors would be necessary for ensuring effective and constructive communication and interpretation of polygenic risk information which, in turn, could have implications for the uptake of any therapeutic recommendations. Recent advances in polygenic risk scoring have major implications for its clinical potential, however, care should be taken to ensure that communication of polygenic risk does not feed into problematic assumptions regarding mental disorders or support reductive interpretations.

A comparison of ten polygenic score methods for psychiatric disorders applied across multiple cohorts

“…Some of these methods (P+T,LDpred and PRS-CS) require a tuning sample, a GWAS cohort with known trait status that is independent of both discovery and target samples, used to select parameters needed to generate the PGSs in the target sample. Briefly, P+T (pruning with a p-value threshold) uses the GWAS effect size estimates as SNP weights and includes independent SNPs (defined by an LD r 2 filter for a given chromosomal window distance) with association p-values lower than a threshold (chosen after application in a tuning sample). P+T is the most commonly used and basic method, and so is the bench-mark method here.…”

Teenagers and Precision Psychiatry: A Window of Opportunity

“…Although clinicians can facilitate teenagers’ empowerment in health contexts, studies indicate that their knowledge of genomics, especially of psychiatric genetics and gene-environment interactions, is limited [40, 41, 46, 47]. These issues are unlikely to lessen with the growing research on prediction of genetic risk for psychiatric conditions (e.g., polygenic risk scores); on the contrary, a growing body of complex information may increase the possibility of misunderstanding and misinterpretation [48]. Improving public understanding of the potential benefits of precision psychiatry and stakeholders’ psychiatric genomic knowledge will move the needle in the right direction.…”

“…However, the ability of teenagers from historically marginalized racial/ethnic communities to enjoy the benefits of translational genomic efforts is likely to be significantly different than that of White teens. As is well-established, biobank and genomic cohorts are overwhelmingly white, resulting in insufficient power to identify complex genetic interactions and polygenic risk scores for racial/ethnic minorities, including for psychiatric conditions [48]. Concurrently, distrust in the medical community has been recognized as a barrier to accessing genomic medicine among African American, Latino, and Indigenous populations [61, 62].…”

Return of Results in a Global Sample of Psychiatric Genetics Researchers: Practices, Attitudes, and Knowledge

“…32 Recently, there has been a significant amount of debate about the utility and ethical implications of using PRS in psychiatry. 33,34,35,36 While some see PRS as a potential tool to help prevent and manage care for psychiatric disorders at both an individual and general population level, others question its utility at an individual level. 35 Respondents in the present study are likely some of the most knowledgeable experts about the utility and limitations of PRS in psychiatry.…”