NIMH Genes to Biology Virtual Workshop

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NIMH Genes to Biology Virtual Workshop

Genes to Biology: Integrative Systematic Approaches for Revealing Biological Functions of Psychiatric Risk Genes & Alleles Virtual Workshop

By National Institute of Mental Health

Date and time

Tuesday, September 22, 2020 · 8am - 1:30pm PDT

Location

Online

About this event

The purpose of this workshop is to stimulate discussions among experts to identify systematic experimental approaches to gain comprehensive insights into psychiatric disease mechanisms based on human genetic findings. This Genes to Biology (G2B) framework is envisioned as a tiered approach from broad, unbiased high-throughput screens to deep, targeted low-throughput investigations. Given that the effects of coding mutations are more readily interpretable, this workshop focuses on identifying current or emerging scalable technologies for surveying the biological impact of all risk alleles in genes with an increased burden of damaging mutations in neurodevelopmental and psychiatric disorders. The hope is to develop a systematic framework for gaining a meaningful biological understanding of the genetic risk underlying psychiatric disorders and make much-needed headway into identifying disease mechanisms.

AGENDA

The agenda for this event is not yet available. The final agenda will be distributed to registered participants when registration closes.

Program Overview:

Meeting Goals:

  • Identify opportunities and challenges for developing a transformative framework to advance the work on systematic functional dissections of psychiatric risk genes.
  • Focus: conceptual approaches, high-throughput technologies, scalable assays, mechanistic and computational inferences.

Panel Discussions:

11:00 am – 12:00 pm: CONCEPTUAL FRAMEWORKS

Presenter(s):

  • Mark Daly, Ph.D., Broad Institute

Panel Moderators:

  • Steve McCarroll, Ph.D., Harvard University
  • Stephan Sanders, B.M.B.S., Ph.D., University of California, San Francisco

12:00 – 1:20 pm: SCALABLE TECHNOLOGIES

Presenters:

  • Kevin Eggan, Ph.D., Harvard University
  • Jay Shendure, M.D., Ph.D., University of Washington
  • Randall Peterson, Ph.D., University of Utah
  • Alexis Battle, Ph.D., Johns Hopkins University

Panel Moderators:

  • Anne Bang, Ph.D., Sanford Burnham Prebys Medical Discovery Institute
  • Kevin Eggan, Ph.D., Harvard University

1:30 – 2:50 pm: FUNCTIONAL ASSAYS/UNDERSTANDING MECHANISMS

Presenters:

  • Guo-li Ming, M.D., Ph.D., University of Pennsylvania
  • Bennett Novitch, Ph.D., University of California, Los Angeles
  • Ryohei Yasuda, Ph.D., Max Planck Florida Institute for Neuroscience
  • Adam Cohen, Ph.D., Harvard University

Panel Moderators:

  • Gavin Rumbaugh, Ph.D., Scripps Research Institute
  • Sergiu Pasca, M.D., University of California, Los Angeles

3:00 – 4:30 pm: FUTURE DIRECTIONS/NEXT STEPS

Panel Moderators:

  • Dan Geschwind, M.D., Ph.D., University of California, Los Angeles
  • Nicole Soranzo, Ph.D., Wellcome Sanger Institute
  • Nevan Krogan, Ph.D., University of California, San Francisco
  • Jennifer Phillips-Cremins, Ph.D., University of Pennsylvania
  • Richard Huganir, Ph.D., Johns Hopkins University
  • Ellen Hoffman, M.D., Ph.D., Yale University
  • Trey Ideker, Ph.D., University of San Diego
  • Olga Troyanskaya, Ph.D., Princeton University

4:30 pm: Adjourn

This workshop will address the following questions:

Conceptual Frameworks:

  • How can we get from genetic leads to meaningful biological insights?
  • How to prioritize genes and alleles for functional follow-up?
  • Should we study risk alleles/haplotypes or risk genes? 
  • Which psychiatric illnesses have a sufficient number of strongly implicated (e.g. genome-wide significant) genes for meaningful large-scale biological follow-up?
  • Should genes/mutations/alleles be assessed in the same or multiple genetic backgrounds?

Scalable Technologies:

  • What do we have to do in the next 5 -10 years?
  • What technologies (in vitro and in vivo) are ready to be scaled for unbiased biological assessment of human risk variants and/or genes? What technologies are near ready or will be ready in the next 3-5 years?
  • What are the advantages and disadvantages of these technologies (in vitro and in vivo) for large-scale screening? What will be missed by current technologies?
  • What is the minimum number of variants/genes that should be assayed to identify the most relevant biological pathways and disease relevant mechanisms?
  • What questions can and cannot be systematically addressed in cells in vitro? What are the most relevant factors to consider?
  • What questions can and cannot be systematically addressed in model organisms in vivo? What are the most relevant factors to consider?
  • What are the strengths and shortcomings of various biological systems for analyzing risk genes and alleles?
  • What are good biological systems and biological contexts for different questions? And what tools?

Understanding Mechanisms:

  • How are the most informative functional assays for high-throughput screening of risk alleles/genes identified? How do these depend on the experimental system?
  • What is possible and meaningful to measure synaptic function in neurons/circuits today? What phenotypes are quantitative enough to support?
  • To what extent should the assays/measures be agnostic to or informed by candidate disease mechanisms?
  • How do we identify convergent downstream biology across various alleles/genes of interest? What are the appropriate controls to ensure the results are meaningful?
  • What type of causal inference and analytical frameworks are needed to identify molecular and cellular features contributing to disease?
  • What computational frameworks (and coordination across projects) are needed to enable integrative analysis of disparate multi-modal datasets for linking various levels of analysis across different experimental systems?

Future Directions & Next Steps:

  • What mechanisms are useful – collaborative networks? Public-private partnerships?
  • How could the results from broad screens inform investigations into disease mechanisms?
  • How do we select and prioritize findings from systematic screens for in-depth, lower-throughput technologies and assays? Does this require central coordination?
  • How can these findings be leveraged to identify druggable molecular targets?
  • How can we accelerate data sharing and integration?
  • What are the data analysis challenges/issues we need to address, especially integrating multi-modal omic data with neuronal/cellular/synaptic measurements?
  • What are the technology development needs?

WEBINAR DETAILS

The workshop will be held via Zoom. The Zoom information has been distributed to registered participants.

If you have any questions or experience any technical issues, please contact Lora Bingaman (lora.bingaman@nih.gov). Thank you.

REGISTRATION

Registration for this event is now closed.

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