From Molecular Insights to
Patient Stratification for
Neurological and Psychiatric Disorders
PROCEEDINGS OF A WORKSHOP
Lisa Bain, Sheena M. Posey Norris, and Clare Stroud, Rapporteurs
Forum on Neuroscience and Nervous System Disorders
Board on Health Sciences Policy
Health and Medicine Division
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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This activity was supported by contracts between the National Academy of Sciences and the Alzheimer’s Association; California Institute for Regenerative Medicine; Cerevel Therapeutics; Cohen Veterans Bioscience; Department of Health and Human Services’ Food and Drug Administration (R13FD005362) and National Institutes of Health (NIH) (75N98019F00769 [Under Master Base HHSN263201800029I]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Environmental Health Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, NIH Blueprint for Neuroscience Research, and NIH BRAIN Initiative; Department of Veterans Affairs (36C24E20C0009); Eisai Inc.; Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Janssen Research & Development, LLC; Karuna Therapeutics; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (DBI-1839674); One Mind; Sanofi; Simons Foundation Autism Research Initiative; Society for Neuroscience; Takeda Pharmaceuticals International, Inc.; and Wellcome Trust. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.1
International Standard Book Number-13: 978-0-309-27755-6
International Standard Book Number-10: 0-309-27755-8
Digital Object Identifier: https://doi.org/10.17226/26468
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Copyright 2022 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2022. From molecular insights to patient stratification for neurological and psychiatric disorders: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/26468.
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1 This text was revised to correct for the complete list of sponsors for this activity.
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PLANNING COMMITTEE ON MOLECULAR INSIGHTS TO PATIENT STRATIFICATION FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS1
STEVEN HYMAN (Co-Chair), The Broad Institute of MIT and Harvard
DIMITRI KRAINC (Co-Chair), Northwestern University
ELINE APPELMANS, Foundation for the National Institutes of Health
PAOLA ARLOTTA, Harvard University
LINDA BRADY, National Institute of Mental Health
BRADFORD CASEY, The Michael J. Fox Foundation for Parkinson’s Research
CAROLE HO, Denali Therapeutics
FRANCES JENSEN, University of Pennsylvania Perelman School of Medicine
BILL MARTIN, Janssen Research & Development
JOHN NGAI, National Institutes of Health BRAIN Initiative
AMIR TAMIZ, National Institute of Neurological Disorders and Stroke
SARAH TISHKOFF, University of Pennsylvania
STACIE WENINGER, FBRI
ALICE ZHANG, Verge Genomics
Health and Medicine Division Staff
CLARE STROUD, Director, Forum on Neuroscience and Nervous System Disorders
SHEENA M. POSEY NORRIS, Program Officer
EDEN NELEMAN, Senior Program Assistant
ANDREW M. POPE, Senior Director, Board on Health Sciences Policy
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1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
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FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1,2
FRANCES JENSEN (Co-Chair), University of Pennsylvania
JOHN KRYSTAL (Co-Chair), Yale University
SUSAN AMARA, National Institute of Mental Health
ELINE APPELMANS, Foundation for the National Institutes of Health
KATJA BROSE, Chan Zuckerberg Initiative
EMERY BROWN, Harvard Medical School and Massachusetts Institute of Technology
JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai
SARAH CADDICK, Gatsby Charitable Foundation
ROSA CANET-AVILÉS, California Institute for Regenerative Medicine
MARIA CARRILLO, Alzheimer’s Association
EDWARD CHANG, University of California, San Francisco
MICHAEL CHIANG, National Eye Institute (from October 2021)
TIMOTHY COETZEE, National Multiple Sclerosis Society
JONATHAN COHEN, Princeton University
BILLY DUNN, Food and Drug Administration
MICHAEL EGAN, Merck Research Laboratories
MICHELLE ELEKONICH, National Science Foundation
NITA FARAHANY, Duke University
BRIAN FISKE, The Michael J. Fox Foundation for Parkinson’s Research (from January 2022)
JOSHUA A. GORDON, National Institute of Mental Health
MAGALI HAAS, Cohen Veterans Bioscience
RICHARD HODES, National Institute on Aging
STUART HOFFMAN, Department of Veterans Affairs
JONATHAN HORSFORD, National Institute of Dental and Craniofacial Research (until December 2021)
YASMIN HURD, Icahn School of Medicine at Mount Sinai
STEVEN HYMAN, The Broad Institute of MIT and Harvard
MICHAEL IRIZARRY, Eisai Inc.
PUSHKAR JOSHI, One Mind
GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism
WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke
HUSSEINI MANJI, Johnson & Johnson
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1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
2 This text was revised to correct for the complete list of members for this activity.
LOUISE MARSHALL, Wellcome Trust (from October 2021)
JOHN NGAI, National Institutes of Health BRAIN Initiative
STEVE PAUL, Karuna Therapeutics
RAYMOND SANCHEZ, Cerevel Therapeutics (from January 2022)
SARAH SHEIKH, Takeda Pharmaceuticals International
DAVID SHURTLEFF, National Center for Complementary and Integrative Health
JOHN SIMS, Eli Lilly and Company
JOHN SPIRO, Simons Foundation Autism Research Initiative
SANTA TUMMINIA, National Eye Institute (until September 2021)
NORA VOLKOW, National Institute on Drug Abuse
ANDREW WELCHMAN, Wellcome Trust (until September 2021)
DOUG WILLIAMSON, Lundbeck
RICHARD WOYCHIK, National Institute of Environmental Health Sciences
STEVIN ZORN, MindImmune Therapeutics, Inc.
Health and Medicine Division Staff
CLARE STROUD, Director, Forum on Neuroscience and Nervous System Disorders
SHEENA M. POSEY NORRIS, Program Officer
CHANEL MATNEY, Program Officer
EDEN NELEMAN, Senior Program Assistant
CHRISTIE BELL, Finance Business Partner
ANDREW M. POPE, Senior Director, Board on Health Sciences Policy
Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.
We thank the following individuals for their review of this proceedings:
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by ELI Y. ADASHI, Brown University. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.
We also thank staff members Lida Beninson and Ryan Murphy for reading and providing helpful comments on this manuscript.
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Contents
Workshop Objectives and Approach
Organization of the Proceedings
Genetic Variation Across Populations and Health Disparities
Improving the Predictive Value of Polygenic Risk Scores in Psychiatry
Addressing the Lack of Diversity in Existing Genomic Datasets
Incorporating Race and Ancestry into Research and Care
Barriers and Solutions to Including Diverse Populations in Human Genomics Research
4 LEVERAGING NEW METHODOLOGIES TO INTERPRET GENETIC DATA IN NEUROLOGICAL AND PSYCHIATRIC DISORDERS
Functional Effects of Coding Variation
Interpreting Genetic Data in Neurological and Psychiatric Disorders
Regulatory Maps, Gene Networks, and High-Throughput Functional Validation
Embracing the Complexity of Linking Genes to Causality
5 IDENTIFYING AND VALIDATING MOLECULAR PATHWAYS USING NEW TECHNOLOGIES FOR HUMAN BIOLOGY
Modeling in Non-Human Primates
CRISPR-Based Functional Genomics in iPSC Models
Integrating Data from a Spectrum of Models to Gain Maximum Insight
6 ENABLING PATIENT STRATIFICATION THROUGH DEEP PHENOTYPING AND BIOMARKER DISCOVERY
Novel Biomarkers Capture the Complexity of Mechanisms
Multimodal Artificial Intelligence-Based Analysis of Disease Progression
Toward Precision Medicine in Mental Health from a Life-Span Perspective
A Regulatory Perspective on Biomarkers
