Ernst Strüngmann Forum

Science is a highly specialized enterprise—one that enables areas of enquiry to be minutely pursued, establishes working paradigms and normative standards, and supports rigor in experimental research. All too often, however, “problems” encountered in research fall outside the scope of any one area of study, and to enable progress, new perspectives are needed to expand conceptualization, increase understanding, and identify pathways for research to pursue.

The Ernst Strüngmann Forum was established in 2006 to address these types of topics. Founded on the tenets of scientific independence and the inquisitive nature of the human mind, we provide a platform for experts to scrutinize topics that require input from multiple areas of expertise. Our gatherings (or Forums) are best thought of as intellectual retreats: existing perspectives are questioned, gaps in knowledge exposed, and strategies are sought collectively to fill these gaps. The results of the entire process are made available to the broad scientific community through the Strüngmann Forum Report series.

In 2019, preparations for this project began when Josh Gordon and Elisabeth Binder approached us with this topic. Cathryn Lewis, Elise Robinson, Stephan Sanders, and Nenad Sestan joined the Program Advisory Committee, which met to transform the proposal into a framework that would support an extended, multidisciplinary discussion. The committee worked together to delineate discussion topics, identify potential participants, and formulate the overarching goals: to identify areas in the translation of genomics to neurobiology where a systematic, consensus-based, and collaborative approach to experimental science could help reveal the key neurobiological mechanisms associated with genetic risk for mental illness and foster translation of this knowledge into clinically useful approaches.

To focus discussion, thematic areas were selected and questions posed for participants to consider (for details, see Binder and Gordon, this volume). To maximize in-person interactions, invited “background papers” were circulated in advance, and from June 26–July 1, 2022, experts from psychiatric and statistical genetics, neurobiology, and clinical psychiatry gathered in Frankfurt.

This volume is organized around the four main thematic areas that guided the Forum: gene discovery, understanding rare variation, understanding common variation, and clinical considerations. Each section contains the background papers in their finalized form (i.e., after peer review and revision) as well as the summary reports of the discussions (Chapters 2, 5, 8, and 12). As one might imagine, a Forum is not a linear process. The initial framework put into place triggered lively debate and helped expose the “gaps” in knowledge. To summarize these, Gordon and Binder highlight open issues that remain to be addressed (see Chapter 16).

An endeavor of this kind—especially one convened during COVID lockdowns—creates unique group dynamics and puts demands on everyone. I wish to thank each person who participated in this Forum for their time, effort, and positive outlook. A special word of thanks goes to the Program Advisory Committee as well as to the authors and reviewers of the background papers. Importantly, the work of the discussion groups’ moderators—Josh Gordon, Naomi Wray, Stephan Sanders, and Cathryn Lewis—and rapporteurs—Angelica Ronald, Hyejung Won, Carrie Bearden, and Lea Davis—deserves special recognition. To support lively debate and transform this into a coherent, multiauthor report is no simple matter. Finally, I extend my appreciation to Josh Gordon and Elisabeth Binder, whose expertise and leadership accompanied the entire project.

The Ernst Strüngmann Forum is able to conduct its work in the service of science and society due to the backing of the Ernst Strüngmann Foundation, established by Dr. Andreas and Dr. Thomas Strüngmann in honor of their father. I also wish to acknowledge the support received from our Scientific Advisory Board as well as the Deutsche Forschungsgemeinschaft, which provided supplemental financial support for this project.

It is never easy to extend the boundaries to knowledge, and long-held views are often difficult to put aside. Yet once such limitations are recognized, the act of formulating strategies to go beyond this point becomes a most invigorating activity. On behalf of everyone involved in this 31st Ernst Strüngmann Forum, I hope this volume will help assist the delineation of strategic approaches that will lead to further discovery and accelerate scientific and clinical progress.

Julia R. Lupp, Director, Ernst Strüngmann Forum
Frankfurt Institute for Advanced Studies Ruth-Moufang-Str. 1,
60438 Frankfurt am Main, Germany
https://esforum.de/

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.

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This chapter highlights paths, processes, and considerations that become important as we build on the initial success of large genome-wide association studies of psychiatric disorders. As such, it largely focuses on research on common genetic variation and human genetic research. It proposes directing research toward interrogating how genetic variation acts on the developing brain. For this reason, it discusses the potential value and pitfalls of using developmental, circuit-based, and quantitative symptom-based phenotypes in parallel to the traditional approach of reliance on binary diagnoses in genetic research designs. With respect to heterogeneity and co-occurrence present in psychiatric disorders, analytic approaches are outlined that can advance understanding, improve gene discovery, and potentially influence nosology. It argues that increasing cohort diversity is nonnegotiable: it is essential to improve gene discovery, translation, social justice, and research equity. Furthermore, a range of methods that interrogate the processes of environmental risk, gene–environment correlation, and gene–environment interaction enable a more accurate understanding of direct genetic effects and of how environments operate together with genetic risk for psychiatric disorders. Far from being a diversion, these environmentally informed methods are likely to catalyze biological insights. To this end, considerations for optimal future experimental study designs are discussed, outlining their characteristics and the prioritized approaches. The overarching goal is to deliver, through gene discovery research, translational benefits for individuals living with neurodevelopmental conditions and psychiatric disorders.

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Decades of twin and family studies have revealed the high heritability of neuropsychiatric disorders, suggesting an important causal role for genetic factors. Over the last decade, genetic studies have linked hundreds of genes and genetic loci to neuropsychiatric disorders as well as to behavior and cognition more broadly. Most large lists of genetic loci associated with disorders have been generated by consortia. These consortia aggregate data from similarly focused studies from around the globe, with historic emphasis on certain areas. This chapter explores what is necessary to deliver refined genetic insights rigorously and efficiently.

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Insisting on a distinction between “environmental” and “genetic” risks for psychiatric disorders is imprecise and can be counterproductive. The effect of a genetic variant on a psychiatric outcome may act through environmental pathways. Environmental exposures encountered in life are partly a consequence of how our own heritable traits and predispositions, or those of our parents, interact with our surroundings. This chapter reviews key methods to establish whether an environmental exposure causes an increase in the risk to develop psychopathology or whether it causes psychopathology to relapse. A set of widely studied environmental risks are reviewed for their impact on psychopathology: bereavement, loss, family strife, childhood maltreatment, childhood sexual abuse, trauma, migration and minority stress, exposure to (substance) abuse, sleep, education, and income.

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The revolution in human genetics has led to the identification of hundreds of rare genetic variants that underlie neuropsychiatric disorders. This technological leap presents both an opportunity and a dilemma for developing new therapies. Monogenic diseases are simpler to study and can be used to develop a road map for progressing from a genetic cause to both an understanding of neurobiology and a disease-modifying therapy. This trajectory involves the development of cellular and animal models, the understanding of the natural history of a disease, and the identification of biomarkers and clinical endpoints.  However, the large number of mutations and the rarity of the diseases requires criteria for prioritization and strategies for connecting these diseases to more common causes of neuropsychiatric disorders. The goal of this chapter is to provide a road map to help prioritize investments that will improve our understanding of rare neuropsychiatric diseases, connect these diseases to common disorders, and help to catalyze the development of new therapies.

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Rare deleterious variants with large effect sizes offer a unique opportunity to understand the pathophysiology of neurodevelopmental and psychiatric disorders and provide insights into mechanism-based therapies. Single gene disorders may, in particular, be addressable with gene-based technologies even in cases where we may not understand the pathophysiology completely, as has been the case for spinal muscular atrophy. This chapter reviews the therapeutics development process in several modalities, including small molecules, antisense oligonucleotides, and viral vector-mediated gene replacement using examples of rare genetic disorders such as tuberous sclerosis complex, Fragile X syndrome, Rett syndrome, and Angelman syndrome. Finally, a strengths, weaknesses, opportunities, and threats (SWOT) analysis is included to guide the use of rare genetic variants to develop treatments. Identification of rare genetic variants has changed the landscape of research in this field; however, to translate these discoveries into rational, mechanism-based, safe, and effective treatments for neurodevelopmental and psychiatric disorders will require building and sustained support of networks/consortia that work closely with patient communities and industry partners.

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Resolving the target genes, pathways, cellular phenotypes, and circuit functions impacted by the hundreds of genomic loci significantly associated with psychiatric disorders is a major challenge. Applications of genomic engineering in human-induced pluripotent stem cells (hiPSCs) and mice are widely used to study the impact of psychiatric risk variants within defined cell types of the brain. As the scale and scope of functional genomic studies expands, so must our ability to resolve the complex interplay of the many risk variants linked to psychiatric disorders. Here we discuss the current state of the field, with particular emphasis on hiPSC and mouse models, which have facilitated efforts to understand the pathophysiology of psychiatric disorders and translate genetic findings into disease-relevant biology in the service of advancing diagnostics and therapeutic development.

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Common allele associations provide the starting point for delineating biological pathways that could progress understanding of psychiatric disorders. Multiple genomic approaches have been synergistically used to identify key contributing biological pathways that show evidence of convergence. Crucial next steps entail identification of causal risk variants, identification of causal risk genes, and identification of causal biological pathways. While a small number of genes could be prioritized and studied using the experimental paradigms applied to rare allele (large-effect) associations, this approach is neither feasible nor relevant for common variant associations where each person at high risk of disease carries a unique portfolio of risk variants, and where risk variants are carried by all of us. New experimental paradigms are needed that exploit the natural genetic variation present in populations and seek to understand why these unique portfolios of risk variants converge to disturb biological homeostasis, which lead to a common disease diagnosis. Recommendations for pathways forward are made, including new experimental paradigms that are specifically focused on combinations of risk-associated variants supported by new brain-specific data resources.

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Over the last 15 years, genome-wide association studies have demonstrated that psychiatric disorders, like other common diseases, are highly polygenic. The traditional toolbox of approaches used to characterize functional effects of causal genetic variants has been constructed for monogenic disease, where a single variant is associated with a high probability of disease risk at some point in the lifetime. This toolbox has limited utility for studying risk variants of small effect. To develop new experimental paradigms requires a deep understanding of polygenic architectures. First, many risk variants have small effect, which means most people with each variant do not have the disease associated with the risk. Disease is associated with carrying a high burden of risk variants, implying that the function of each risk variant is dependent on its genetic context. Second, each person diagnosed with a common disease is expected to carry a unique, or almost unique, portfolio of risk variants. Yet despite this heterogeneous genetic architecture, diagnostic classes do have some biological validity. Third, as observed for other common diseases, we expect there to be multiple pathways that contribute to increased risk of disease across many cell types and impacting over the lifespan. The key question then is how to penetrate this polygenic complexity.

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Genome-wide association studies (GWASs) have been integral to our understanding of the polygenic architecture of psychiatric disorders, yet distilling disease biology from GWAS remains a challenge because GWAS-identified genomic regions often contain dozens of variants with highly correlated structure. The majority of variants within these loci are located within the noncoding genome, so their functional consequences are not immediately apparent. Moreover, to characterize thousands of such variants requires a highly scalable experimental approach. Such systematic interrogation of the functional consequences of variants is enabled by population-scale molecular assays (e.g., quantitative trait loci) or scalable genomic perturbation assays (e.g., massively parallel reporter assays or CRISPR screens). This review describes available genomic resources and cutting-edge experimental approaches that have been adopted to infer functional consequences of risk variants. Additionally, it outlines gaps in defining causal variants, linking variants to target genes, interrogating combinatorial effects of variants within the polygenic background, and considering the context-specific nature of variants. Extended efforts to fill these gaps will enable more comprehensive interpretation of GWAS and ultimately reveal the fundamental biological context behind polygenic psychiatric disorders.

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Psychiatric disorders are highly polygenic, with estimated contributions from hundreds to thousands of causal variants, across the allelic spectrum. Interpretation of such a widely distributed genetic risk architecture is a daunting challenge, as no single locus can explain disease etiology, yet it is also critical for mechanistic understanding and clinical translation. Systems biology can begin to contextualize genetic risk variation within our understanding of the hierarchical organization of the human brain, encompassing its cognate underlying cellular pathways and gene regulatory networks, cell types and states, cell–cell interactions, circuit-level function, and ultimately behavior. This chapter provides an overview of how high-throughput molecular “omic” profiling coupled with network-level inference can provide a framework for biological contextualization of established genetic risk factors to elucidate convergent disease mechanisms. Successes are highlighted leveraging systems biology to prioritize synaptic and chromatin complex genes, and next steps are enumerated to further the translational utility of these approaches.

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Over the past two decades, genomics research has been enormously successful in identifying specific genes, pathways, and mechanisms that play a role in the development of psychiatric and neurodevelopmental disorders. The translation of these findings into the clinical setting has been slow but steady. Current clinical advances range from identifying genetic etiologies for neurodevelopmental disorders to pharmacogenomic dosing guidelines for psychiatric medications. Many more advances can be anticipated, given the paradigm-shifting knowledge produced by the field. Principally, genomics research has produced neurobiological hypotheses that are likely to yield therapeutic advances only in the long term. Nonetheless, opportunities to improve clinical care also exist in the near term. This chapter evaluates and prioritizes these opportunities in terms of their feasibility and potential impact. Barriers to the successful translation of these findings are identified and areas for research highlighted to support their translation into clinical settings.

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Large-scale genome-wide association studies have demonstrated that psychiatric phenotypes are highly polygenic, involving thousands of loci of individually small effect. Polygenic risk scores (PRSs), which sum these effects, can provide a composite index of an individual’s genetic vulnerability. There has been growing interest in the potential use of PRS for clinical applications and advancing precision psychiatry. Here, I summarize the prospects for implementing PRSs in a range of potential use cases including predicting disease risk, reducing diagnostic uncertainty, forecasting prognosis, guiding treatment selection, informing genetic counseling, and validating prevention strategies. PRSs represent one of the most robust biomarkers in psychiatry, but as reviewed here, several important challenges remain before they can be used in clinical practice. Future work will need to address the limited predictive value of current scores, the Eurocentric bias of available data, the need to optimize the integration of PRS with other risk factors, and the validation of actionable risk-stratified interventions. Efforts to translate PRS to real-world applications will also require research using an implementation science framework. Nevertheless, the potential value of PRS for improving clinical care in psychiatry justifies investments in research and implementation strategies to overcome these challenges.

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From the earliest days of predictive genetic testing, concerns have been expressed about the potential negative consequences of informing people of their genetic risks. Most studies to date have suggested that the impact of genetic testing is generally benign, albeit with some variation across individuals. There is, however, little evidence about the effects of predictive testing in neuropsychiatric disorders, especially for the major syndromes. As polygenic approaches to the prediction of genetic risk are refined and considered for introduction to the clinic, it will be important to consider potential adverse effects, including stigmatization, demoralization, therapeutic nihilism, and self-fulfilling prophecies. Prior to adopting polygenic prediction of vulnerability to neuropsychiatric disorders, response to treatment, and negative outcomes such as side effects and suicidality, careful evaluation of the risks and benefits of such technologies is required.

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The world’s first specialist psychiatric genetic counseling clinic opened in 2012. Despite ample evidence that psychiatric genetic counseling produces excellent outcomes for patients, even in the absence of any genetic testing, this service is still not widely available clinically despite efforts to train practitioners in the delivery of this intervention. Patients could benefit now from the delivery of psychiatric genetic counseling (even in the absence of testing), and we have an ethical duty to consider how to ensure that the infrastructure is in place to ensure optimal outcomes for patients. This is particularly important as we move closer toward the clinical application of genetic testing in the context of psychiatric conditions. It is important to consider how such testing might be deployed and to ensure that any testing is delivered according to the established practices for psychiatric genetic counseling that produce the best patient outcomes. This chapter reviews evidence that patients benefit from psychiatric genetic counseling and discusses the barriers to its broader implementation.

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As discussed throughout this volume, our understanding of the genetic basis of psychiatric disorders has advanced tremendously. This understanding now needs to be translated into actionable biology to help patients. The chapters in this volume represent an earnest attempt to clarify just how much our understanding has progressed, and what might be necessary to complete the translation process. As we noted in Chapter 1, during the course of the Forum, four distinct groups captured the progress to date and discussed pathways forward for next steps, tackling a set of questions the groups posed of themselves and then set about to answer. Here we will recap the progress made toward answering these questions in the four groups, summarizing the principal conclusions. We will then close by considering some cross-cutting themes that link ideas across multiple groups.

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