SUMMARY The global burden of mental illness, including autism spectrum disorders (ASD), intellectual disability, epilepsy, Tourette disorder, schizophrenia and bipolar disorder, is enormous, whether measured in health care expenditures, lost productivity, or personal suffering. Unfortunately, there is a striking lack of insight into the underlying molecular biology of these syndromes. However, recent advances in gene discovery are setting the stage for a transformation in the understanding of these psychiatric disorders. Understanding pathobiology and developing novel treatments is becoming increasingly dependent on knowledge of biological networks of multiple types, including physical interactions among proteins and synthetic­lethal and epistatic interactions among genes. Here we seek support for a new effort, the Psychiatric Cell Map Initiative (PCMI, www.pcmi.ucsf.edu), aimed at comprehensively understanding these complex interactions in psychiatric disorders and how they differ between diseased and healthy states. While we will focus on ASD in this proposal, this work will establish a paradigm to investigate other psychiatric disorders in future work. The PCMI is a multi­campus initiative of the University of California, involving UC San Francisco, UC San Diego and UC Berkeley, which leverages genomics, proteomics, high­throughput sequencing, advanced network mapping, computational analysis, and research platforms developed by multiple PCMI investigators over the past decade. Thus primed, these platforms will be tuned to efficiently generate, assemble, and analyze molecular networks linked to ASD, in relevant cell types, with a view towards pathway and network­based personalized therapy. Specifically, over the next five years the PCMI will seek to catalyze major phase transitions in ASD research and therapy by (1) Comprehensively mapping the networks of physical interactions among proteins linked to ASD, revealing the protein complexes and higher­order molecular units underlying ASD in multiple cell types of the human brain; (2) Mapping the parallel networks of synthetic­lethal and epistatic interactions among ASD genes using CRISPR­based approaches; (3) Establishing the robust computational methodology, end­user software, and databases for assembly and use of ASD cell network maps in both basic and clinical modalities; (4) Translating molecular insights into an understanding of higher order phenotypes; (5) Building a critical mass of leading investigators focused on psychiatric disorders worldwide to expand PCMI into a global coordinated partnership; and (6) Training the current and next­generation of scientists in Network Biology and its applications to research focused on psychiatric disorders.

NARRATIVE Although the past few years have ushered in much success in identifying the genes linked to autism spectrum disorders (ASD), we need to move beyond simply cataloguing component genes in order to gain a mechanistic and actionable understanding of ASD and other psychiatric disorders. More specifically, it is critical to understand the many interactions between these genes and the proteins they encode, and how these complex networks are connected to the underlying pathobiology of ASD. To address this challenge, the Psychiatric Cell Map Initiative (PCMI, www.pcmi.ucsf.edu) will apply systematic approaches to comprehensively map the molecular networks that underlie ASD and translate them to higher order biological insights, which will form a key resource for precision medicine.