In Search of Causality: From Neuropsychiatric Genetics to Pathophysiology

September 23, 2022, 10:00am – 6:00pm | New York Genome Center

Open workshop organized as a joint effort between New York Genome Center (NYGC), Columbia University, UCSF, University of Oxford, UCLA, and Simons Foundation Autism Research Initiative (SFARI)

Conference Chairs: Kelsey Martin (SFARI, UCLA) ● Stephan Sanders (Oxford, UCSF) ● Thomas Lehner (NYGC)

Friday, September 23rd, 2022
10:00 AM – 6:00 PM

This will be a VIRTUAL meeting via Zoom.

The past decade has seen immense progress in identifying hundreds of causal factors for neuropsychiatric disorders, mostly in the form of genetic variants. However, limited progress has been made in identifying the pathophysiological processes that connect cause to phenotypic effect. Should such causal processes be established, they would hold considerable potential for therapeutic development in a field where advances are desperately needed. Establishing these causal relationships is complicated by the limited ability to assay the living human brain, the absence of clear endpoints in experimental model systems, and the tendency of the causal factors towards pleiotropic effects, only some of which contribute to neuropsychiatric phenotypes. In the face of these challenges, how do we establish causality?

Exploring this question is made more challenging by the complexity of the brain and insufficiently accurate models of how behavior is encoded in cells and circuits. Fundamental questions remain about which developmental stages, brain regions, cell types, biological pathways, and circuits are involved and whether these are adequately represented in cellular and animal model systems. The absence of clear answers to these questions makes it hard to isolate one variable for study (e.g., investigating a circuit necessitates a decision about which developmental stages to query; investigating developmental stages require choices of brain regions) and leads to heterogeneous data, which complicates integrative analysis.

This workshop will explore the challenges and opportunities in delineating the etiology of neuropsychiatric disorders, and the inherent conceptual and epistemological limitations of developing causal models of brain function in health and disease. Participants will explore the nature of causality against our limited understanding of brain function across levels of organizational complexity including integrating information across levels of analyses from genes to cells to circuits to behavior.

This meeting will take place on September 23rd, 2022 and will be virtual. Expected outcomes are a critical assessment of the state of the art, a prioritized list of recommendations for future research and the identification of areas in need of collaboration across specialties. The proceedings will be summarized in a position paper.

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