Exploring and Exploiting Genetic Risk for Psychiatric Disorders (Strüngmann Forum Reports)

Contents
List of Contributors
Preface
1 Exploring and Exploiting Genetic Risk for Psychiatric Disorders
	Discovering Genetic Loci and Describing Genetic Architecture
	Understanding Biology
	Clinical Applications
	The Ernst Strüngmann Forum: Exploring and Exploiting Genetic Risk for Psychiatric Disorder
Gene Discovery
	2 Delineating Additional Risk Factors
		Abstract
		Background
		Alternative Phenotypes
		Heterogeneity and Co-occurrence
		Allelic Frequency Spectrum
		Focusing on Diversity
		Environmental Risk and Gene–Environment Relationships
		Future Experimental Design
		Acknowledgments
	3 Data Collection
		Abstract
		Identifi cation of Genetic Variants in Neuropsychiatric Disorders
		Natural Selection and Genomic Architecture
		Completing Discovery
		Increasing Genetic Associations across the Frequency Spectrum to Fill in Missing Biology
		Improving Global Representation
		Conclusion
	4 Environmental Risk and Gene–Environment Relationships in Psychiatric Disorders
		Abstract
		Introduction
		Genetic Risk and Environmental Risk Are Not Mutually Exclusive
		Establishing Whether Environmental Risk Factors Are Causal
		Historically Emphasized and Plausible Environmental Risk Exposures
		Conclusion
Understanding Rare Variation
	5 Rare Variants
		Abstract
		Introduction
		Prioritizing Genes and Loci for Neurobiological Investigation
		Convergent Neurobiology
		Models to Interrogate Genetic Loci
		Requirements for Clinical Trials
		Implementation
		Conclusions and Major Outcomes
		Acknowledgments
	6 Promises and Challenges of Precision Medicine in Rare Neurodevelopmental Disorders
		Abstract
		Introduction
		Genetic Landscape of Autism Spectrum Disorder
		Therapeutic Modalities
		SWOT Analysis of Rare Variants
		Disclosures
	7 Experimental Model Systems for Rare and Common Variants
		Abstract
		Introduction
		Heritability of Psychiatric Disorders
		Functional Genomic Studies of Psychiatric Disorder Pathophysiology
		Fundamental Questions Lacking Answers
		Summary
Understanding Common Variation
	8 Common Alleles
		Abstract
		Introduction
		Pathway: Common Risk Allele to Causal Variant
		Pathway: Causal Risk Variant to Gene
		Pathway: Gene to Function and Phenotype
		Pathway: Context
		Recommendations
	9 Hypotheses of How Common Variants Create Risk for Psychiatric Disorders
		Abstract
		Introduction
		The Different Facets of Polygenicity
		The Relationship between Polygenicity and Disorder
		Experimental Designs that Embrace Polygenicity
		Conclusion
		Acknowledgment
	10 From Common Variant to Function
		Abstract
		Introduction
		What Is the Defi nition of Causal Variants?
		Population-Scale Molecular Assays to Link Variants to Genes
		Functional Genomic Approaches to Annotate Variants
		Beyond Cataloging
		Conclusion
	11 Contextualizing Convergent Common Variant Mechanisms through Systems Biology
		Abstract
		Introduction
		State of Convergence
		Molecular Hierarchies and the Human Brain
		Network-Level Inference
		What Has Systems Biology Taught Us about Psychiatric Genetics?
		How Do We Move Systems Analyses of Psychiatric Genetics Forward?
		Conclusions
		Acknowledgments
Clinical Considerations
	12 Maximizing Near-Term Clinical Opportunities for Psychiatric Genetics
		Abstract
		Introduction
		Near-Term Opportunities and Challenges for Rare Copy Number and Sequence Variants
		Near-Term Opportunities and Challenges for Polygenic Scores
		The Impact of Genetic Counseling with and without Genetic Testing on the Clinical Management of Mental Illness
		Barriers to the Application of Genetics in Clinical Mental Health Practice
		Guiding Principles for Future Research and Implementation
		Conclusion
	13 The Use of Polygenic Risk Scores in Clinical Psychiatry
		Abstract
		Introduction
		Use Case I: Predicting Risk of Psychiatric Disorder
		Use Case II: Reducing Diagnostic Uncertainty
		Use Case III: Predicting Prognosis
		Use Case IV: Stratifi cation to Enhance Treatment Selection
		Other Potential Clinical Uses
		Conclusions and Remaining Challenges
	14 Ethical Challenges Associated with Advances in Genetic Prediction of Neuropsychiatric Disorders
		Abstract
		Introduction
		Psychosocial Impact of Neuropsychiatric Genetic Testing
		Ethical Concerns about Advances in Genetic Prediction of Neuropsychiatric Disorders
		Ethical Challenges around Genetic Prediction of Other Outcomes: Treatment Response, Side Effects, and Suicide
		Conclusion
	15 Psychiatric Genetic Counseling
		Abstract
		Introduction
		Genetic Counseling: History, Models, and Theories
		Psychiatric Genetic Counseling
		Genetic Testing for Psychiatric Conditions
		Insights into the Outcomes of Genetic Testing for Psychiatric Conditions
		Barriers to Adoption and Implementation of Psychiatric Genetic Counseling
		Summary
	16 Concluding Summary
		Introduction
		Delineating Additional Risk Factors
		Rare Variation
		Common Variation
		Clinical Opportunities
		Cross-Cutting Themes
		Conclusion: Strategic Coordination to Speed Progess
Bibliography
Subject Index
Strüngmann Forum Report Series