Ernst Strüngmann Forum

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Exploring and Exploiting Genetic Risk
for Psychiatric Disorders

Edited by Joshua A. Gordon and Elisabeth Binder

Even before a basic understanding of genetic principles became widely available, careful clinical observation identified the hereditary underpinnings of mental illness (Kendler 2021). Building on these early observations, large-scale twin, adoption, and family studies ultimately solidified the notion that genetic factors contribute strongly to psychiatric illness. With the advent of robust molecular tools and large-scale collaborative consortia, the structure of genetic risk as well as many of the individual genetic factors conferring this risk have been elucidated. Indeed, the pace of progress in psychiatric genetics has been dizzying. No sooner is an article published that identifies yet another tranche of loci or genes linked to a disorder than it is out of date, and new advances have been posted to preprint servers.
Despite this remarkable progress, critics continue to maintain that the genetic revolution has led neither to increased understanding of the nature of mental illness nor to the development of novel therapies for these disabling conditions. Indeed, it is important to recognize the limits of progress in psychiatric genetics and to consider carefully how success in understanding and identifying genetic risk can be translated into understanding and treatment of mental illness. Such was the purpose of the Ernst Strüngmann Forum on Exploring and Exploiting Genetic Risk for Psychiatric Disorders, and such is the purpose of this book which arises from those proceedings. The Forum brought together experts in psychiatric and statistical genetics, neurobiology, and clinical psychiatry to discuss the state of psychiatric genetics and chart a path forward for further discovery and translation in the field.

Exploring and Exploiting Genetic Risk for Psychiatric Disorders

June 26–July 1, 2022

Frankfurt am Main, Germany

Joshua A. Gordon and Elisabeth Binder, Chairpersons

Program Advisory Committee

Elisabeth Binder, Joshua A. Gordon, Cathryn Lewis, Julia Lupp, Elise Robinson, Stephan Sanders, and Nenad Sestan

Goal of the Forum

To identify areas in the translation of genomics to neurobiology where a systematic, consensus-based and collaborative approach to experimental science can help reveal the key neurobiological mechanisms associated with genetic risk for mental illness and foster translation of this knowledge into clinically useful approaches.

Context

The genetic basis of psychiatric illnesses was for decades a mystery despite considerable evidence for heritability. After many failed attempts at hunting for psychiatric risk genes, the realization that psychiatric disorders are polygenic, coupled with collaborative efforts to amass immense samples and characterize them with genome-wide association studies (GWAS), has finally revealed the genetic architecture of schizophrenia, bipolar disorder, depression, and autism, among other diagnoses. Hundreds of risk loci for these disorders have been identified, the vast majority of them being common alleles of very small effect sizes – raising risk by a few percentage points rather than several fold, as in mendelian disorders (even those with incomplete penetrance). Add to these hundreds of common alleles several dozen rare mutations of larger effect sizes (mostly copy number variants with multiple genes deleted or duplicated, with the exception of some monogenic forms of autism with intellectual disability) and you have many clues to the origins of psychiatric disease risk, but very little understanding of how to turn these clues into neurobiological understanding of the chain of events leading to mental illness.

In attempting to forge a pathway leading from this increased genetic understanding through neurobiological understanding to novel therapies, the field faces several important controversies:

Whether and how to explore additional genetic and non-genetic risk factors.
How to exploit these genetic clues in order to identify and characterize the underlying molecular, cellular, circuit, and systems-level biology of relevance to psychiatric disorders.
Whether and how our current genetic understanding can be used in the near term to improve clinical science and clinical practice.

These controversies play out amidst a backdrop of excitement that originates from an explosion of promising new tools in other areas of psychiatric science. These include the development of large datasets (e.g., the UK Biobank, iPSYCH, psychENCODE, and others) and powerful computational approaches to studying them; a plethora of molecular tools to engineer human and animal experimental systems and causally test hypotheses across multiple levels of analysis; and mathematical methods to analyze complex and interacting network phenomenon at the molecular and circuit levels. All of these factors converge upon the possibility that discussions focused on establishing a framework for prioritizing and evaluating progress in furthering the translation of genomics to neurobiology and treatment will be fruitful in the near term.

To this end, the Ernst Strüngmann Forum will bring together experts in epidemiological and statistical genetics, systems biology, experimental and translational neuroscience, and translational and clinical psychiatry to discuss how best to explore and exploit our newfound and hard-won understanding of the genetic risk for psychiatric disorders.

This Forum is supported by the Deutsche Forschungsgemeinschaft

The German Research Foundation

Framework for Discussion

Discussion at the Forum will focus on the following four themes, each with associated overarching issues and key questions. Cutting across all four groups will be consideration of common concerns, including the heterogeneity within and across psychiatric disorders, the need to set priorities given limited resources, and the importance of making the most of available opportunities.

Group 1: Delineating additional risk factors

Issue: We have identified hundreds of risk loci for some disorders. Yet much of the risk for these disorders remains unexplained, leaving us with uncertainty regarding the importance of and approach to identifying additional risk factors.

How do we recognize when locus discovery for a given disorder has reached the point of diminishing returns? How does that differ by variant type?
How do we expand the diversity of our samples, in particular with regard to ancestry, and how do we integrate across ethnic groups?
How do we explore the space of environmental risk and gene-environment relationships?
What are the comparative roles of categorical diagnoses and quantitative phenotyping in genomic studies?

Group 2: Common alleles: Pathways forward

Issue: The majority of genetic risk for psychiatric disorders seems to come from common alleles with small effect sizes, likely numbering in the hundreds to thousands. These common alleles of small effect are challenging as a starting point for understanding neurobiology.

How do you go from GWAS locus to causative alleles and its functional impact on gene transcription? How do you define success?
How do we prioritize genetic findings for neurobiological investigation, e.g., between GWAS hits, or between rare and common alleles?
How do we understand the collective impact of common variant risk? How do we integrate rare variant risk into this?
What experimental model systems are needed to interrogate polygenic risk?

Group 3: Rare alleles: Exploring neurobiology

Issue: Hundreds of genes are associated with psychiatric disorders through variants of large effect. How do we progress from a list of genes to insight into cell type, circuit-level action, and developmental time and, ultimately, novel therapeutics?

How do we prioritize between genes for neurobiology investigation? What should the relative priority be between rare and common variation?
What are the strategies for testing for convergence and divergence in mechanism between large effect size mutations, and between rare and common alleles? How do we distinguish meaningful convergence?
What experimental model systems are showing promise to interrogate rare variant risk and how can they be leveraged?
How do we recognize when there is a sufficient neurobiological basis to begin to explore therapeutics?

Group 4: Maximizing Near-Term Clinical Opportunities

Issue: There is a pressing need to develop clinical applications that leverage genetic associations to psychiatric disorders. What can we do now? What can we envision doing in the near future? How do we get there?

Can we conceive of situations in which polygenic risk scores have will be useful?
How might integration of biomarkers, environmental risk, rare variants, or other factors be used to improve upon the utility of polygenic risk scores?
How should genetic risk be communicated considering the heterogeneity of the phenotypic spectrum and the affect size? What sorts of clinical decisions might be affected?
How could genetic risk inform the design of clinical trials? Consider the role of pharmacogenetics, stratification, etc.