The Lancet Commission on global mental health and sustainable development

The Lancet, Год журнала: 2018, Номер 392(10157), С. 1553 - 1598

Опубликована: Окт. 1, 2018

Язык: Английский

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Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Cell, Год журнала: 2020, Номер 180(3), С. 568 - 584.e23

Опубликована: Янв. 23, 2020

Язык: Английский

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Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Cell, Год журнала: 2019, Номер 179(7), С. 1469 - 1482.e11

Опубликована: Дек. 1, 2019

Язык: Английский

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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

Science, Год журнала: 2018, Номер 362(6420)

Опубликована: Дек. 13, 2018

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments transcriptomic organization diseased brains are limited. In this work, we integrated genotypes RNA sequencing brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, bipolar disorder, as well controls. More than 25% the transcriptome exhibits differential splicing or expression, isoform-level changes capturing largest effects enrichments. Coexpression networks isolate disease-specific neuronal alterations, microglial, astrocyte, interferon-response modules defining previously unidentified neural-immune mechanisms. We genomic data to perform a transcriptome-wide association study, prioritizing loci likely mediated by cis on expression. This characterization molecular pathology across three major disorders provides resource mechanistic insight therapeutic development.

Язык: Английский

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Comprehensive functional genomic resource and integrative model for the human brain

Science, Год журнала: 2018, Номер 362(6420)

Опубликована: Дек. 13, 2018

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 adult brain across 1866 individuals. The contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles many cell types; quantitative-trait loci (QTLs); further QTLs associated with chromatin, splicing, cell-type proportions. Integration shows that varying proportions largely account cross-population variation (with >88% reconstruction accuracy). It also allows building gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic scores identifies key pathways disorders.

Язык: Английский

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All for One and One for All: Mental Disorders in One Dimension

American Journal of Psychiatry, Год журнала: 2018, Номер 175(9), С. 831 - 844

Опубликована: Апрель 6, 2018

In both child and adult psychiatry, empirical evidence has now accrued to suggest that a single dimension is able measure person’s liability mental disorder, comorbidity among disorders, persistence of disorders over time, severity symptoms. This general psychopathology been termed “p,” because it conceptually parallels already familiar behavioral scientists clinicians: the “g” factor intelligence. As g reflects low high ability, p represents severity, with thought disorder at extreme. The unites all disorders. It influences present/absent status on hundreds psychiatric symptoms, which modern nosological systems typically aggregate into dozens distinct diagnoses, in turn three overarching domains, namely, externalizing, internalizing, psychotic experience finally one from high: p. Studies show higher person scores p, worse fares measures family history illness, brain function, childhood developmental history, life impairment. A may help account for ubiquitous nonspecificity psychiatry: multiple share same risk factors biomarkers often respond therapies. Here, authors summarize unidimensional idea, review research demystify statistical models, articulate some implications prevention clinical practice, outline transdiagnostic agenda. [AJP AT 175: Remembering Our Past We Envision Future October 1910: Study Association Insanity Grace Helen Kent A.J. Rosanoff:

Язык: Английский

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Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments

Neuron, Год журнала: 2019, Номер 102(1), С. 75 - 90

Опубликована: Апрель 1, 2019

Язык: Английский

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Predictive Processing: A Canonical Cortical Computation

Neuron, Год журнала: 2018, Номер 100(2), С. 424 - 435

Опубликована: Окт. 1, 2018

Язык: Английский

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Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Science, Год журнала: 2018, Номер 362(6420)

Опубликована: Дек. 14, 2018

INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. development the a highly complex process, this process reliant on precise regulation molecular cellular events grounded in spatiotemporal transcriptome. Disruption can lead to neuropsychiatric disorders. RATIONALE regulatory, epigenomic, transcriptomic features human have not been comprehensively compiled across time, regions, or cell types. Understanding etiology disorders requires knowledge just endpoint differences between healthy diseased brains but also developmental contexts which these arise. Moreover, an emerging body research indicates that many aspects physiology are well recapitulated model organisms, therefore it necessary be understood broader context developing adult brain. RESULTS Here we describe generation analysis variety genomic data modalities at tissue single-cell levels, including transcriptome, DNA methylation, histone modifications multiple regions ranging age from embryonic through adulthood. We observed widespread transition beginning during late fetal consisting sharply decreased regional differences. This reduction coincided with increases transcriptional signatures mature neurons expression genes associated dendrite development, synapse neuronal activity, all were temporally synchronous neocortical areas, as myelination oligodendrocytes, asynchronous. MEF2C , SATB2 TCF4 genetic associations brain-related traits disorders, converged small number modules exhibiting spatial specificity. CONCLUSION generated applied our dataset document epigenetic changes then related those major These allowed identify genes, types, gene coexpression modules, loci where disease risk might converge, demonstrating utility providing new insights into disease. Spatiotemporal dynamics risks. Human begins continues adulthood (top). Integrating (bottom left) revealed age- type–specific properties global patterns dynamics, middle). variation (brown, high; purple, low) regulatory elements brains, signatures, right; gray circles indicate enrichment corresponding among module genes). Relationships depicted panel do correspond specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus thalamus; AMY, amygdala.

Язык: Английский

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Trans Effects on Gene Expression Can Drive Omnigenic Inheritance

Cell, Год журнала: 2019, Номер 177(4), С. 1022 - 1034.e6

Опубликована: Май 1, 2019

Язык: Английский

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