Spatial and Temporal Mapping of De Novo Mutations in Schizophrenia to a Fetal Prefrontal Cortical Network
Open accessAbstract
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
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Many high-risk SZ genes form protein interactions in fetal dorsolateral and ventrolateral PFC.
“form protein interactions in fetal dorsolateral (DL) and ventrolateral PFC 162”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [162]
Many high-risk SZ genes are functionally implicated in synaptic transmission.
“and/or are functionally implicated in synaptic transmission 162,163.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [162]
A seeded co-expression approach has been used to identify risk convergence in schizophrenia, identifying fetal development of the prefrontal cortex as a point of convergence for de novo mutations.
“A seeded co-expression approach has also been used to identify risk convergence in schizophrenia, identifying fetal development of the prefrontal cortex as a point of convergence for de novo mutations115.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [115]
Approaches integrating spatio-temporal transcriptome with gene mutation discoveries have implicated projection neurons in prefrontal and primary motor-somatosensory cortex during mid-fetal development in autism spectrum disorder and frontal cortex during fetal development in schizophrenia.
“In particular, these approaches have implicated the projection neurons in the prefrontal and primary motor-somatosensory cortex during mid-fetal development in autism spectrum disorder and the frontal cortex during fetal development in schizophrenia (Gulsuner et al., 2013; Kang et al., 2011; Lin et al., 2015; Parikshak et al., 2013; State and Sestan, 2012; Willsey et al., 2013).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Gulsuner et al., 2013
The developing prefrontal cortex has a distinct gene network that contains a number of schizophrenia genes.
“Regionally enriched transcriptomes form a co-expression network; for example, the developing prefrontal cortex has a distinct gene network that contains a number of schizophrenia genes (Gulsuner et al., 2013).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Gulsuner et al., 2013
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- Authors
- Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., Rippey, C., Shahin, H., Braff, D., Cadenhead, K. S., Calkins, M. E., Dobie, D. J., Freedman, R., Green, M., Greenwood, T., Gur, R. E., Gur, R. C., Lazzeroni, L., Light, G., Nuechterlein, K., Olincy, A., Radant, A., Ray, A., Schork, N., Seidman, L. J., Siever, L., Silverman, J., Stone, W. S., Sugar, C., Swerdlow, N., Tsuang, D., Tsuang, M., Turetsky, B., Aduroja, T., Allen, T., Bradford, L. D., Calkins, M. E., Devlin, B., Edwards, N. B., Ganguli, R., Go, R. C. P., Gur, R. E., Gur, R. C., Kwentus, J., Lahti, A. C., Lyons, P., Mathos, K., May, R., McLeod-Bryant, S., McEvoy, J. P., Montgomery-Barefield, L., Nimgaonkar, V. L., O’Jile, J., Santos, A., Savage, R. M., Swanson, C. L., Wilson, W., Nimgaonkar, V. L., Go, R. C. P., Savage, R. M., Swerdlow, N. R., Gur, R. E., Braff, D. L., King, M.-C., & McClellan, J. M.
- Affiliations
- University of Washington (US)
- Bethlehem University (PS)
- University of Alabama at Birmingham (US)
- University of California San Diego (US)
- University of Pennsylvania (US)
- Corresponding author
- King, Mary-Claire
- ORCID
- Walsh, Tom
- Lee, Ming K.
- Casadei, Silvia
- Cadenhead, Kristin S.
- Freedman, Robert
- Greenwood, Tiffany
- Lazzeroni, Laura
- Light, Gregory
- Nuechterlein, Keith
- Seidman, Larry J.
- Silverman, Jeremy
- Stone, William S.
- Sugar, Catherine
- Tsuang, Debby
- Tsuang, Ming
- Devlin, Bernie
- Ganguli, Rohan
- Lahti, Adrienne C.
- Lyons, Paul
- McEvoy, Joseph P.
- Wilson, William
- King, Mary-Claire
- McClellan, Jon M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 154
- Issue
- 3
- Pages
- 518-529
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3894107
- OpenAlex
- W2119608950
- Cited by
- 536
- References
- 97
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 13 · 2023: 29 · 2022: 27 · 2021: 48 · 2020: 50 · 2019: 43 · 2018: 44 · 2017: 54 · 2016: 63 · 2015: 57 · 2014: 63 · 2013: 15
- FWCI
- 46.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH083849, U01MH096844, R01MH093533, R01MH083756, R01MH086135, R01MH084071, R01MH083989)
- National Cancer Institute (R01CA157744)
- National Institute of General Medical Sciences (T32GM007266)
- Fogarty International Center (R03TW008696)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- schizophrenia, de novo mutations, prefrontal cortex, fetal brain development, neurogenesis, gene expression profiling, protein-protein interaction network, neuronal migration, synaptic transmission, neurodevelopmental disorders, gene expression mapping
- MeSH terms
- Brain, DNA Mutational Analysis, Female, Humans, Male, Mutation, Schizophrenia, Transcription, Genetic, Prefrontal Cortex, Databases, Genetic, Gene Regulatory Networks, Neurogenesis, Transcriptome, Protein Interaction Maps
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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