Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Li, Mingfeng, Santpere, Gabriel, Imamura Kawasawa, Yuka, Evgrafov, Oleg V., Gulden, Forrest O., Pochareddy, Sirisha, Sunkin, Susan M., Li, Zhen, Shin, Yurae, Zhu, Ying, Sousa, André M. M., Werling, Donna M., Kitchen, Robert R., Kang, Hyo Jung, Pletikos, Mihovil, Choi, Jinmyung, Muchnik, Sydney, Xu, Xuming, Wang, Daifeng, Lorente-Galdos, Belen, Liu, Shuang, Giusti-Rodríguez, Paola, Won, Hyejung, de Leeuw, Christiaan A., Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Hu, Ming, Jin, Fulai, Li, Yun, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Posthuma, Danielle, Reimers, Mark A., Levitt, Pat, Weinberger, Daniel R., Hyde, Thomas M., Kleinman, Joel E., Geschwind, Daniel H., Hawrylycz, Michael J., State, Matthew W., Sanders, Stephan J., Sullivan, Patrick F., Gerstein, Mark B., Lein, Ed S., Knowles, James A. and Sestan, Nenad 2018. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science 362 (6420) , eaat7615. 10.1126/science.aat7615

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Abstract

INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. RATIONALE The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. RESULTS Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C, SATB2, and TCF4, with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. CONCLUSION We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	BrainSpan Consortium, PsychENCODE Consortium, PsychENCODE Developmental Subgroup
Publisher:	American Association for the Advancement of Science
ISSN:	0036-8075
Date of First Compliant Deposit:	9 January 2019
Date of Acceptance:	15 November 2018
Last Modified:	10 Nov 2024 16:00
URI:	https://orca.cardiff.ac.uk/id/eprint/118230

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