Chromatin accessibility during human first-trimester neurodevelopment DOI Creative Commons
Camiel C.A. Mannens, Lijuan Hu, Peter Lönnerberg

et al.

Nature, Journal Year: 2024, Volume and Issue: unknown

Published: May 1, 2024

Abstract The human brain develops through a tightly organized cascade of patterning events, induced by transcription factor expression and changes in chromatin accessibility. Although gene across the developing has been described at single-cell resolution 1 , similar atlases accessibility have primarily focused on forebrain 2–4 . Here we describe paired entire during first trimester (6–13 weeks after conception). We defined 135 clusters used multiomic measurements to link candidate cis -regulatory elements expression. number accessible regions increased both with age along neuronal differentiation. Using convolutional neural network, identified putative functional factor-binding sites enhancers characterizing subtypes. applied this model linked ESRRB elucidate its activation mechanism Purkinje cell lineage. Finally, linking disease-associated single nucleotide polymorphisms elements, validated pathogenic mechanisms several diseases midbrain-derived GABAergic neurons as being most vulnerable major depressive disorder-related mutations. Our findings provide more detailed view key regulatory underlying emergence types comprehensive reference for future studies related neurodevelopment.

Language: Английский

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders DOI Creative Commons
Phil H. Lee, Verneri Anttila, Hyejung Won

et al.

Cell, Journal Year: 2019, Volume and Issue: 179(7), P. 1469 - 1482.e11

Published: Dec. 1, 2019

Language: Английский

Citations

1199
Longitudinal Assessment of Mental Health Disorders and Comorbidities Across 4 Decades Among Participants in the Dunedin Birth Cohort Study DOI Creative Commons
Avshalom Caspi, Renate Houts, Antony Ambler

et al.

JAMA Network Open, Journal Year: 2020, Volume and Issue: 3(4), P. e203221 - e203221

Published: April 21, 2020

Importance

Mental health professionals typically encounter patients at 1 point in patients’ lives. This cross-sectional window understandably fosters focus on the current presenting diagnosis. Research programs, treatment protocols, specialist clinics, and journals are oriented to diagnoses, assumption that diagnosis informs about causes prognosis. study tests an alternative hypothesis: people with mental disorders experience many different kinds of across diagnostic families, when followed for 4 decades.

Objective

To describe disorder life histories first half course.

Design, Setting, Participants

cohort involved participants born New Zealand from 1972 1973 who were enrolled population-representative Dunedin Study. Participants observed birth age 45 years (until April 2019). Data analyzed May 2019 January 2020.

Main Outcomes Measures

Diagnosed impairing assessed 9 times ages 11 years. Brain function was through neurocognitive examinations conducted 3 years, neuropsychological testing during childhood adulthood, midlife neuroimaging-based brain age.

Results

Of 1037 original (535 male [51.6%]), 1013 had data available. The proportions meeting criteria a as follows: 35% (346 975) 15 50% (473 941) 18 51% (489 961) 21 48% (472 977) 26 46% (444 969) 32 45% (429 955) 38 44% (407 927) onset occurred by adolescence 59% (600 1013), eventually affecting 86% (869 1013) midlife. By 85% (737 869) accumulated comorbid diagnoses. adolescent-onset subsequently presented more past-year assessments (r = 0.71; 95% CI, 0.68 0.74;P < .001) met diverse 0.64; 0.60 0.67;P .001). Confirmatory factor analysis summarizing decades identified general psychopathology, p-factor. Longitudinal analyses showed high p-factor scores (indicating extensive histories) antedated poor functioning −0.18; −0.24 −0.12;P .001), accompanied childhood-to-adulthood cognitive decline −0.11; −0.17 −0.04;P associated older 0.14; 0.07 0.20;P

Conclusions Relevance

These findings suggest shift among successive disorders. present study, alongside nationwide Danish registers, inform life-course perspective cautions against overreliance diagnosis-specific research clinical protocols.

Language: Английский

Citations

487
Genetic Causes and Modifiers of Autism Spectrum Disorder DOI Creative Commons
Lauren Rylaarsdam, Alicia Guemez‐Gamboa

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: Aug. 20, 2019

Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD highly genetically heterogeneous and may be caused by both inheritable de novo gene variations. In past decade, hundreds genes have been identified that contribute to serious deficits communication, social cognition, behavior patients often experience. However, these only account for 10-20% cases, with similar pathogenic variants diagnosed on very different levels spectrum. this review, we will describe genetic landscape discuss how modifiers such as copy number variation, single nucleotide polymorphisms, epigenetic alterations likely play a key role modulating phenotypic spectrum patients. We also consider can alter convergent signaling pathways lead impaired neural circuitry formation. Lastly, review sex-linked clinical implications. Further understanding mechanisms crucial comprehending developing novel therapies.

Language: Английский

Citations

460
Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders DOI Creative Commons
Patrick F. Sullivan, Daniel H. Geschwind

Cell, Journal Year: 2019, Volume and Issue: 177(1), P. 162 - 183

Published: March 1, 2019

Language: Английский

Citations

400
Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort DOI Open Access
Youwen Qin, Aki S. Havulinna, Yang Liu

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(2), P. 134 - 142

Published: Feb. 1, 2022

Language: Английский

Citations

322
A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles DOI
Nancy Y. A. Sey,

Benxia Hu,

Won Mah

et al.

Nature Neuroscience, Journal Year: 2020, Volume and Issue: 23(4), P. 583 - 593

Published: March 9, 2020

Language: Английский

Citations

262
Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders DOI Open Access
Yash Patel, Nadine Parker, Jean Shin

et al.

JAMA Psychiatry, Journal Year: 2020, Volume and Issue: 78(1), P. 47 - 47

Published: Aug. 26, 2020

Importance

Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these is not well understood.

Objective

To determine neurobiologic correlates of between cases and controls 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum (ASD), bipolar (BD), major depressive (MDD), obsessive-compulsive (OCD), schizophrenia.

Design, Setting, Participants

Profiles were generated using T1-weighted magnetic resonance images. Similarity interregional profiles cell-specific gene expression those the investigated each disorder. Next, principal component analysis was used to reveal a shared profile difference Analysis for coexpression, clustering, enrichment genes associated with disorders conducted. Data conducted June December 2019. included 145 cohorts drawn from ENIGMA consortium. numbers as follows: ADHD: 1814 1602; ASD: 1748 1770; BD: 1547 3405; MDD: 2658 3572; OCD: 2266 2007; schizophrenia: 2688 3244.

Main Outcomes Measures

Interregional controls.

Results

A total 12 721 15 600 controls, ranging ages 2 89 years, this study. specific pyramidal (CA1) cells, astrocytes (except BD), microglia OCD); collectively, gene-expression 3 cell types explain 25% 54% variance thickness. Principal (48% explained); 1 that pyramidal-cell (explaining 56% variation). Coexpression analyses clusters: (1) prenatal cluster enriched involved neurodevelopmental (axon guidance) processes (2) postnatal synaptic activity plasticity-related processes. These clusters all

Conclusions Relevance

In study, multiple implicate common role development functioning cerebral cortex

Language: Английский

Citations

203
Glial cells in schizophrenia: a unified hypothesis DOI
Andrea Dietz, Steven A. Goldman,

Maiken Nedergaard

et al.

The Lancet Psychiatry, Journal Year: 2019, Volume and Issue: 7(3), P. 272 - 281

Published: Nov. 6, 2019

Language: Английский

Citations

198
Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses DOI
Thomas D. Als, Mitja Kurki, Jakob Grove

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(7), P. 1832 - 1844

Published: July 1, 2023

Language: Английский

Citations

164
Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities DOI Creative Commons
Travis T. Mallard, Richard Karlsson Linnér, Andrew D. Grotzinger

et al.

Cell Genomics, Journal Year: 2022, Volume and Issue: 2(6), P. 100140 - 100140

Published: June 1, 2022

Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology treatment psychopathology. Here, we combine transdiagnostic dimensional approaches genetic discovery for the first time, conducting a novel multivariate genome-wide association study eight psychiatric symptoms disorders broadly related mood disturbance psychosis. We identify two liabilities that distinguish between common forms psychopathology rarer serious mental illness. Biological annotation revealed divergent architectures differentially implicated prenatal neurodevelopment neuronal function regulation. These findings inform models psychopathology, as they suggest psychotic present in illness may reflect difference kind rather than merely degree.

Language: Английский

Citations

77