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Comprehensive functional genomic resource and integrative model for the human brain.

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.

SUBMITTER: Wang D

PROVIDER: S-EPMC6413328 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Comprehensive functional genomic resource and integrative model for the human brain.

Wang Daifeng D Liu Shuang S Warrell Jonathan J Won Hyejung H Shi Xu X Navarro Fabio C P FCP Clarke Declan D Gu Mengting M Emani Prashant P Yang Yucheng T YT Xu Min M Gandal Michael J MJ Lou Shaoke S Zhang Jing J Park Jonathan J JJ Yan Chengfei C Rhie Suhn Kyong SK Manakongtreecheep Kasidet K Zhou Holly H Nathan Aparna A Peters Mette M Mattei Eugenio E Fitzgerald Dominic D Brunetti Tonya T Moore Jill J Jiang Yan Y Girdhar Kiran K Hoffman Gabriel E GE Kalayci Selim S Gümüş Zeynep H ZH Crawford Gregory E GE Roussos Panos P Akbarian Schahram S Jaffe Andrew E AE White Kevin P KP Weng Zhiping Z Sestan Nenad N Geschwind Daniel H DH Knowles James A JA Gerstein Mark B MB

Science (New York, N.Y.) 20181201 6420

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 w ...[more]

PMID: 30545857

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Project description:BackgroundDiffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.MethodsWe performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.ResultsUnsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.ConclusionsThe integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Dataset Information

Comprehensive functional genomic resource and integrative model for the human brain.

Publications

Comprehensive functional genomic resource and integrative model for the human brain.

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