Elisabeth Binder,Max Planck Institute of Psychiatry, Munich, Germany
Joshua A. Gordon, National Institute of Mental Health, Bethesda, MD, U.S.A.
Cathryn Lewis,Division of Genetics and Molecular Medicine, King’s College London, U.K.
Julia Lupp, Ernst Strüngmann Forum, 60438 Frankfurt, Germany
Elise Robinson,Broad Institute, Cambridge, MA, U.S.A.
Stephan Sanders, School of Medicine, University of California, San Francisco, U.S.A.
Nenad Sestan, Department of Neuroscience, Yale University, New Haven, CT, U.S.A.
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.
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:
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 31st 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.
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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.
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.
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.
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?
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?
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