The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

A Jeremy Willsey; Montana T Morris; Sheng Wang; Helen R Willsey; Nawei Sun; Nia Teerikorpi; Tierney B Baum; Gerard Cagney; Kevin J Bender; Tejal A Desai; Deepak Srivastava; Graeme W Davis; Jennifer Doudna; Edward Chang; Vikaas Sohal; Daniel H Lowenstein; Hao Li; David Agard; Michael J Keiser; Brian Shoichet; Mark von Zastrow; Lennart Mucke; Steven Finkbeiner; Li Gan; Nenad Sestan; Michael E Ward; Ruth Huttenhain; Tomasz J Nowakowski; Hugo J Bellen; Loren M Frank; Mustafa K Khokha; Richard P Lifton; Martin Kampmann; Trey Ideker; Matthew W State; Nevan J Krogan

doi:10.1016/j.cell.2018.06.016

The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

Cell. 2018 Jul 26;174(3):505-520. doi: 10.1016/j.cell.2018.06.016.

Authors

A Jeremy Willsey¹, Montana T Morris², Sheng Wang², Helen R Willsey³, Nawei Sun², Nia Teerikorpi⁴, Tierney B Baum², Gerard Cagney⁵, Kevin J Bender⁶, Tejal A Desai⁷, Deepak Srivastava⁸, Graeme W Davis⁹, Jennifer Doudna¹⁰, Edward Chang¹¹, Vikaas Sohal¹², Daniel H Lowenstein⁶, Hao Li¹³, David Agard¹³, Michael J Keiser¹⁴, Brian Shoichet¹⁵, Mark von Zastrow¹⁶, Lennart Mucke¹⁷, Steven Finkbeiner¹⁸, Li Gan¹⁷, Nenad Sestan¹⁹, Michael E Ward²⁰, Ruth Huttenhain²¹, Tomasz J Nowakowski²², Hugo J Bellen²³, Loren M Frank²⁴, Mustafa K Khokha²⁵, Richard P Lifton²⁶, Martin Kampmann²⁷, Trey Ideker²⁸, Matthew W State²⁹, Nevan J Krogan³⁰

Affiliations

¹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jeremy.willsey@ucsf.edu.
² Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
⁶ Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Gladstone Institutes, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
¹¹ Department of Neurological Surgery, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
¹² Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA.
¹³ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁴ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁵ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁶ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁷ Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
¹⁸ Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁹ Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
²⁰ National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
²¹ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
²² Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
²³ Departments of Molecular and Human Genetics and Neuroscience, Neurological Research Institute at TCH, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
²⁴ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
²⁵ Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
²⁶ Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065, USA.
²⁷ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
²⁸ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
²⁹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA.
³⁰ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: nevan.krogan@ucsf.edu.

Abstract

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.

Keywords: convergence; genetics; interactome; network; neurodevelopmental disorder; pathway; proteomics; psychiatric cell map initiative; psychiatric disorder; psychiatry; systems biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Chromosome Mapping / methods*
Gene Regulatory Networks / genetics
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study / methods
Genomics / methods
Humans
Neurobiology / methods
Neurodevelopmental Disorders / genetics*
Neuropsychiatry
Systems Biology / methods*

Abstract

Publication types

MeSH terms

Grants and funding