Comprehensive functional genomic resource and integrative model for the human brain

Daifeng Wang, Shuang Liu, Jonathan Warrell, Hyejung Won, Xu Shi, Fabio C.P. Navarro, Declan Clarke, Mengting Gu, Prashant Emani, Yucheng T. Yang, X. Min, Michael J. Gandal, Shaoke Lou, Jing Zhang, Jonathan J. Park, Chengfei Yan, Suhn KyongRhie, Kasidet Manakongtreecheep, Holly Zhou, A. Aparna NathaMette Peters, Eugenio Mattei, Dominic Fitzgerald, Tonya Brunetti, Jill Moore, Yan Jiang, Kiran Girdhar, Gabriel E. Hoffman, Selim Kalayci, Zeynep H. Gümüş, Gregory E. Crawford, Panos Roussos, Schahram Akbarian, Andrew E. Jaffe, Kevin P. White, Zhiping Weng, Nenad Sestan, Daniel H. Geschwind, James A. Knowles, Mark B. Gerstein

Research output: Contribution to journalArticle

Abstract

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ∼79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia).We embed this network into an interpretable deep-learning model, which improves disease prediction by ∼6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

Original languageEnglish (US)
Article number1266
JournalScience
Volume362
Issue number6420
DOIs
StatePublished - Dec 14 2018

ASJC Scopus subject areas

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    Wang, D., Liu, S., Warrell, J., Won, H., Shi, X., Navarro, F. C. P., Clarke, D., Gu, M., Emani, P., Yang, Y. T., Min, X., Gandal, M. J., Lou, S., Zhang, J., Park, J. J., Yan, C., KyongRhie, S., Manakongtreecheep, K., Zhou, H., ... Gerstein, M. B. (2018). Comprehensive functional genomic resource and integrative model for the human brain. Science, 362(6420), [1266]. https://doi.org/10.1126/science.aat8464