week 3: Andreassen et al (2023) new insights fom last decade in psychiatric genetics

How has the understanding of the causes of mental illness evolved from the “nature vs nurture” debate?

The understanding has moved beyond a simple “either/or” debate. It is now understood that both genetic variations (”nature”) and environmental factors (“nurture”) contribute to the risk of mental illness in closely intertwined processes.

What does the concept of “heritability” mean in the context of psychiatric disorders?

Heritability means that a substantial proportion of the variation in the risk of developing mental illness is attributable to differences in genetic factors between individuals.

What are “common variants” and how have Genome-Wide Association Studies (GWAS) been used to identify them?

Common variants are genetic differences that occur frequently in the population. GWAS systematically screen millions of these variants to find associations with specific traits or disorders by comparing their frequency in individual with the disorder versus controls.

What is “polygenicity” and how does it relate to the genetic architecture of psychiatric disorders?

Polygenicity refers to the number of common genetic variants that influence a phenotype. Psychiatric disorders are highly polygenic, meaning thousands of common variants, each with a small effect, collectively influence the risk of illness.

What is “pleiotrophy” and how is it observed in the genetic risk for psychiatric disorders?

Pleiotrophy is when a single genetic variants or set of variants influences multiple seemingly unrelated traits or disorders. In psychiatric genetics, this is seen in the high degree of shared genetic risk and overlap across different psychiatric diagnosis categories.

How do genetic findings challenge the current diagnosis classification systems (nomological) for psychiatric disorders?

Genetic findings reveal significant overlap and shared genetic risk across different psychiatric disorders, which challenges the current categorical diagnostic systems and supports the notion of a more dimensional framework for understanding psychopathology.

What are polygenic risk scores (PRS) and what is their current clinical utility for psychiatric disorders?

Polygenic Risk Scores (PRS) are tools that predict individual genetic susceptibility to illness based on the combined effects of many generic variants. Currently, they do not provide clinically actionable information for general population screening but may have potential utility in specific clinical settings or subgroups.

How might genetic findings inform pharmacological research and drug development for psychiatric disorders?

Genetic findings can point to core biological mechanisms and identify potential drug targets. Drugs with genetic support appear to have a higher success rate in clinical development, and genetic analysis can inform the potential repurposing of existing drugs.

What are some of the challenges in applying genetic risk prediction tools across different populations?

Challenges include differences in allele frequencies and genetic variants correlations (LD structure) across populations, as well as potential differences in environmental contexts and diagnostic presentations. This highlights the need for greater diversity in genetic studies.

Beyond psychiatric disorders, what other types of traits and diseases share genetic influences with mental illness?

Psychiatric disorders share genetic influences with a range of behavioural and somatic traits and diseases, including brain structures, cognitive function, immunological phenotypes, and cardiovascular disease.

How have advancements in psychiatric genetics changed our understanding of psychiatric disorders?

Recent progress in psychiatric genetics has fundamentally shifted the understanding of psychiatric disorders from a simple “nature vs. Nurture” debate to one acknowledging the complex interplay between genetic and environmental factors. Historically, the familial aggregation of mental illness was noted, and twin and adoption studies confirmed substantial heritability for major psychiatric disorders. However, the latest research, particularly large-scale Genome-Wide Association Studies (GWAS), has revealed that these disorders are influenced by thousands of genetic variants working in concert, rather than single “disease gene”. Most of these variants are common in the population, meaning everyone had some degree of genetic risk for each psychiatric disorders. This understanding challenges the notion of psychiatric disorders as entirely distinct entities and highlights shared genetic influences between different diagnoses, as well as with behavioural and physical health conditions.

What are the key findings regarding the genetic architecture of psychiatric disorders?

Psychiatric disorders are now understood to have a highly polygenic architecture, meaning they are influenced by numerous common genetic variants, each with a tiny effect. While these common variants account for a significant portion of the heritability (ranging from approximately 5% to 25% for major disorders based on SNP-based heritability estimates), they still don’t explain the full genetic risk. Large-scale GWAS have identified of genomic loci associated with psychiatric disorders, but these only explain a fraction of the estimated common variant heritability. Additionally, research using Whole Exome Sequencing (WES) has identified an excess burden of rare protein-truncating and demanding variants in genes under strong evolutionary constraint, particularly in disorders like ASD and SZ, contributing to the genetic risk.

How do common and rare genetic variants contribute to psychiatric disorder risk?

Both common and rare play a role in the genetic risk for psychiatric disorders, although their contributions differ. Common variants, which are prevalent in the population, collectively exert a large influence through their additive effects (polygenicity). These are typically incentivised through large GWAS. Rare variants, which are less frequent, can have larger individual effects and are often identified through sequencing studies like WES. While common variants contribute significantly to the overall genetic liability, specific rare variants can confer a higher individual risk, particularly in disorders like ASD and SZ. The combination f these common and rare variants, along with environmental factors, shapes an individual’s overall risk profile.

What is the concept of shared genetic risk and pleiotropy in psychiatric disorders?

A major insight from recent genetic studies is the significant degree of shared genetic risk and pleiotropy across psychiatric disorders. Pleiotrophy refers to a single genetic variant influencing multiple seemingly unrelated traits or disorders. Genetic correlation analyses have shown substantial positive correlations between the genetic risk for various psychiatric disorders, Suggesting that they exist on genetic continuum rather than being completely distinct entities. This genetic overlap aligns with the observed clinical and epidemiological overlap and challenges the traditional cegorical diagnostic systems. Furthermore, genetic risk for psychiatric disorders also overlap with genetic variation in behavioural traits and physical health conditions, highlighting a broader genetic interconnectedness.

How does genetic research inform our understanding of the biological mechanisms underlying psychiatric disorders?

Identifying genetic variants associated with psychiatric disorders provides clues about the underlying biological mechanisms. While the precise mechanisms are still being unravelled, the most convincing biological interpretation of genetic findings, particularly in ASD and SZ, implicates altered synaptic function. Gene-set analyses can also highlight pathways and targets potentially involved in the disorders, some of which are targets of existing drugs, suggesting opportunities for drug repurposing or the development of new therapies with genetic support, which tends to have a higher success rate in clinical development.

How do polygenic Risk Score (PRSs) work, and what is their current clinical utility in psychiatry?

Polygenic Risk Scores (PRSS) are tools that aggregate the effects of thousands of common genetic variants associated with a particular disorder to estimate an individual’s genetic susceptibility. They are calculated based on findings form large GWAS. Currently, PRSs for psychiatric disorders do not provide clinically actionable information for general population screening due to their relatively low predictive accuracy. This means that many individuals with a high PRSs will not develop the disorder, and many who do develop the disorder have a PRS closer to the average. However, PRSs may have potential utility in specific clinical contexts, such as predicting psychosis risk in individuals already identified as being at high risk due to carrying large-effect rare variants. The predicative power of PRSs is expected to improve with large and more diverse genetic datasets.

What are the challenges and opportunities for clinical translation on psychiatric genetics?

Despite the significant scientific progress, translating genetic findings into routine clinical practice in psychiatry faces several challenges. These included improving the predictive accuracy of PRSs, ensuring equitable predictive performance across different ancestral groups (as current datasets are predominantly European), and addressing significant ethical concerns regarding the use and potential misuse of genetic information. The heterogeneity and overlapping nature of psychiatric disorders themselves, as currently defined by diagnostic criteria, also pose a challenge for disorder-specific PRS development. However, the increasing availability of large, deeply phenotypes genetic datasets, combined with decreasing costs of genotyping, offers opportunities for improved genetic prediction, risk stratification, informing clinical decision-making, and potentially refining diagnostic classification systems in the future.

What are the ethical considerations surrounding the use of genetic information for psychiatric disorders?

The increasing accessibility of genetic information, including through direct-to-consumer genotyping services, raises important ethical considerations. Consumers can access their raw genotypes and compute PRS for psychiatric disorders, often without adequate guidance on interpretation. Given the common misconception that genetic testing is deterministic, there is a risk of misinterpreting results, potentially leading to anxiety, stigma, or other harmful outcomes. As genetic information becomes more integrated into healthcare, it it crucial to educate both clinicians and patients about the potential uses and limitations of genetic risk information and to establish clear guidelines and regulations to ensure responsible and ethical use.