Publications by authors named "Daniel H Geschwind"

382 Publications

Oxytocin for Autism Spectrum Disorder - Down, but Not Out.

N Engl J Med 2021 10;385(16):1524-1525

From the Departments of Neurology, Psychiatry, and Human Genetics and the Institute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMe2110158DOI Listing
October 2021

Maternal immune activation during pregnancy alters postnatal brain growth and cognitive development in nonhuman primate offspring.

J Neurosci 2021 Oct 1. Epub 2021 Oct 1.

Department of Psychiatry and Behavioral Sciences, University of California, Davis

Human epidemiologic studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys () born to MIA-treated dams (=14) injected with a modified form of the viral mimic, Polyinosinic:polycytidylic acid (Poly IC) at the end of the first trimester. Control dams received saline injections at the same gestational time points (=10) or were untreated (=4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal magnetic resonance imaging revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates (NHPs) and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical MIA models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are carried out in rodents, the NHP provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a NHP MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0378-21.2021DOI Listing
October 2021

Postnatal immune activation causes social deficits in a mouse model of tuberous sclerosis: Role of microglia and clinical implications.

Sci Adv 2021 Sep 17;7(38):eabf2073. Epub 2021 Sep 17.

Departments of Neurobiology, Psychology, and Psychiatry, Integrative Center for Learning and Memory, and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.

[Figure: see text].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abf2073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448451PMC
September 2021

Defining the nature of human pluripotent stem cell-derived interneurons via single-cell analysis.

Stem Cell Reports 2021 Oct 9;16(10):2548-2564. Epub 2021 Sep 9.

Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA, USA; Broad Stem Cell Center for Regenerative Medicine, UCLA, Los Angeles, CA, USA; Molecular Biology Institute, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Intellectual and Developmental Disabilities Research Center, UCLA, Los Angeles, CA, USA. Electronic address:

The specification of inhibitory neurons has been described for the mouse and human brain, and many studies have shown that pluripotent stem cells (PSCs) can be used to create interneurons in vitro. It is unclear whether in vitro methods to produce human interneurons generate all the subtypes found in brain, and how similar in vitro and in vivo interneurons are. We applied single-nuclei and single-cell transcriptomics to model interneuron development from human cortex and interneurons derived from PSCs. We provide a direct comparison of various in vitro interneuron derivation methods to determine the homogeneity achieved. We find that PSC-derived interneurons capture stages of development prior to mid-gestation, and represent a minority of potential subtypes found in brain. Comparison with those found in fetal or adult brain highlighted decreased expression of synapse-related genes. These analyses highlight the potential to tailor the method of generation to drive formation of particular subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2021.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514853PMC
October 2021

Brain-trait-associated variants impact cell-type-specific gene regulation during neurogenesis.

Am J Hum Genet 2021 09 19;108(9):1647-1668. Epub 2021 Aug 19.

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456186PMC
September 2021

Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome.

Mol Autism 2021 08 3;12(1):54. Epub 2021 Aug 3.

Children's Hospital Los Angeles, Los Angeles, CA, USA.

Background: Sleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12-30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome.

Methods: To test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12).

Results: Children with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls.

Limitations: This study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG-routinely ordered for epilepsy monitoring-opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology.

Conclusions: We have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13229-021-00460-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336244PMC
August 2021

Three decades of ASD genetics: building a foundation for neurobiological understanding and treatment.

Hum Mol Genet 2021 Oct;30(20):R236-R244

Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASDs) for which microarrays, whole exome sequencing and whole genome sequencing have yielded over a hundred causal loci. Genome-wide association studies in ASD have also been fruitful, identifying 5 genome-wide significant loci thus far and demonstrating a substantial role for polygenic inherited risk. Approaches rooted in systems biology and functional genomics have increasingly placed genes implicated by risk variants into biological context. Genetic risk affects a finite group of cell-types and biological processes, converging primarily on early stages of brain development (though, the expression of many risk genes persists through childhood). Coupled with advances in stem cell-based human in vitro model systems, these findings provide a basis for developing mechanistic models of disease pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab176DOI Listing
October 2021

Coexpression network architecture reveals the brain-wide and multiregional basis of disease susceptibility.

Nat Neurosci 2021 09 22;24(9):1313-1323. Epub 2021 Jul 22.

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Gene networks have yielded numerous neurobiological insights, yet an integrated view across brain regions is lacking. We leverage RNA sequencing in 864 samples representing 12 brain regions to robustly identify 12 brain-wide, 50 cross-regional and 114 region-specific coexpression modules. Nearly 40% of genes fall into brain-wide modules, while 25% comprise region-specific modules reflecting regional biology, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. Schizophrenia and autism genetic risk are enriched in brain-wide and multiregional modules, indicative of broad impact; these modules implicate neuronal proliferation and activity-dependent processes, including endocytosis and splicing, in disease pathophysiology. We find that cell-type-specific long noncoding RNA and gene isoforms contribute substantially to regional synaptic diversity and that constrained, mutation-intolerant genes are primarily enriched in neurons. We leverage these data using an omnigenic-inspired network framework to characterize how coexpression and gene regulatory networks reflect neuropsychiatric disease risk, supporting polygenic models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-021-00887-5DOI Listing
September 2021

Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders.

Nat Commun 2021 06 25;12(1):3968. Epub 2021 Jun 25.

Neurogenetics Program, Department of Neurology, David Geffen School of Medicine University of California, Los Angeles, CA, USA.

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer's disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-24243-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233376PMC
June 2021

Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes.

Nat Commun 2021 06 25;12(1):3958. Epub 2021 Jun 25.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA.

Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration. Most knowledge on astrocyte biology is based on studies of mouse models and the similarities and differences between human and mouse astrocytes are insufficiently characterized, presenting a barrier in translational research. Based on analyses of acutely purified astrocytes, serum-free cultures of primary astrocytes, and xenografted chimeric mice, we find extensive conservation in astrocytic gene expression between human and mouse samples. However, the genes involved in defense response and metabolism show species-specific differences. Human astrocytes exhibit greater susceptibility to oxidative stress than mouse astrocytes, due to differences in mitochondrial physiology and detoxification pathways. In addition, we find that mouse but not human astrocytes activate a molecular program for neural repair under hypoxia, whereas human but not mouse astrocytes activate the antigen presentation pathway under inflammatory conditions. Here, we show species-dependent properties of astrocytes, which can be informative for improving translation from mouse models to humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-24232-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233314PMC
June 2021

C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.

Neuron 2021 07 15;109(14):2275-2291.e8. Epub 2021 Jun 15.

Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Department of Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Electronic address:

C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2021.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298293PMC
July 2021

Cell type hierarchy reconstruction via reconciliation of multi-resolution cluster tree.

Nucleic Acids Res 2021 Sep;49(16):e91

Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

A wealth of clustering algorithms are available for single-cell RNA sequencing (scRNA-seq) data to enable the identification of functionally distinct subpopulations that each possess a different pattern of gene expression activity. Implementation of these methods requires a choice of resolution parameter to determine the number of clusters, and critical judgment from the researchers is required to determine the desired resolution. This supervised process takes significant time and effort. Moreover, it can be difficult to compare and characterize the evolution of cell clusters from results obtained at one single resolution. To overcome these challenges, we built Multi-resolution Reconciled Tree (MRtree), a highly flexible tree-construction algorithm that generates a cluster hierarchy from flat clustering results attained for a range of resolutions. Because MRtree can be coupled with most scRNA-seq clustering algorithms, it inherits the robustness and versatility of a flat clustering approach, while maintaining the hierarchical structure of cells. The constructed trees from multiple scRNA-seq datasets effectively reflect the extent of transcriptional distinctions among cell groups and align well with levels of functional specializations among cells. Importantly, application to fetal brain cells identified subtypes of cells determined mainly by maturation states, spatial location and terminal specification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkab481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450107PMC
September 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Aug;78(8):993-1003

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
August 2021

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

Brain 2021 May 29. Epub 2021 May 29.

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab204DOI Listing
May 2021

Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation.

Nat Neurosci 2021 07 20;24(7):941-953. Epub 2021 May 20.

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, it remains poorly understood as to how these variants influence gene regulation. To model the functional impact of common genetic variation on the noncoding genome during human cortical development, we performed the assay for transposase accessible chromatin using sequencing (ATAC-seq) and analyzed chromatin accessibility quantitative trait loci (QTL) in cultured human neural progenitor cells and their differentiated neuronal progeny from 87 donors. We identified significant genetic effects on 988/1,839 neuron/progenitor regulatory elements, with highly cell-type and temporally specific effects. A subset (roughly 30%) of chromatin accessibility-QTL were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type-specific chromatin accessibility-QTL and brain-relevant genome-wide association data, we were able to fine-map and identify regulatory mechanisms underlying noncoding neuropsychiatric disorder risk loci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-021-00858-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254789PMC
July 2021

A neurogenetic analysis of female autism.

Brain 2021 07;144(6):1911-1926

Department of Pediatrics, Yale School of Medicine, New Haven, CT 06510, USA.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320285PMC
July 2021

Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility.

Sci Rep 2021 Mar 11;11(1):5748. Epub 2021 Mar 11.

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by motor neuron (MN) loss. Multiple genetic risk factors have been identified, implicating RNA and protein metabolism and intracellular transport, among other biological mechanisms. To achieve a systems-level understanding of the mechanisms governing ALS pathophysiology, we built gene co-expression networks using RNA-sequencing data from control human spinal cord samples, identifying 13 gene co-expression modules, each of which represents a distinct biological process or cell type. Analysis of four RNA-seq datasets from a range of ALS disease-associated contexts reveal dysregulation in numerous modules related to ribosomal function, wound response, and leukocyte activation, implicating astrocytes, oligodendrocytes, endothelia, and microglia in ALS pathophysiology. To identify potentially causal processes, we partitioned heritability across the genome, finding that ALS common genetic risk is enriched within two specific modules, SC.M4, representing genes related to RNA processing and gene regulation, and SC.M2, representing genes related to intracellular transport and autophagy and enriched in oligodendrocyte markers. Top hub genes of this latter module include ALS-implicated risk genes such as KPNA3, TMED2, and NCOA4, the latter of which regulates ferritin autophagy, implicating this process in ALS pathophysiology. These unbiased, genome-wide analyses confirm the utility of a systems approach to understanding the causes and drivers of ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85061-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970949PMC
March 2021

Long-term maturation of human cortical organoids matches key early postnatal transitions.

Nat Neurosci 2021 03 22;24(3):331-342. Epub 2021 Feb 22.

Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-021-00802-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109149PMC
March 2021

Pre-existing conditions in Hispanics/Latinxs that are COVID-19 risk factors.

iScience 2021 Mar 12;24(3):102188. Epub 2021 Feb 12.

Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Coronavirus disease 2019 (COVID-19) has exposed health care disparities in minority groups including Hispanics/Latinxs (HL). Studies of COVID-19 risk factors for HL have relied on county-level data. We investigated COVID-19 risk factors in HL using individual-level, electronic health records in a Los Angeles health system between March 9, 2020, and August 31, 2020. Of 9,287 HL tested for SARS-CoV-2, 562 were positive. HL constituted an increasing percentage of all COVID-19 positive individuals as disease severity escalated. Multiple risk factors identified in Non-Hispanic/Latinx whites (NHL-W), like renal disease, also conveyed risk in HL. Pre-existing nonrheumatic mitral valve disorder was a risk factor for HL hospitalization but not for NHL-W COVID-19 or HL influenza hospitalization, suggesting it may be a specific HL COVID-19 risk. Admission laboratory values also suggested that HL presented with a greater inflammatory response. COVID-19 risk factors for HL can help guide equitable government policies and identify at-risk populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879099PMC
March 2021

Evolutionary conservation and divergence of the human brain transcriptome.

Genome Biol 2021 01 29;22(1):52. Epub 2021 Jan 29.

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.

Background: Mouse models have allowed for the direct interrogation of genetic effects on molecular, physiological, and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human- or primate-specific and therefore which components can be faithfully recapitulated in mouse models.

Results: We compare conservation of co-expression in 116 independent data sets derived from human, mouse, and non-human primate representing more than 15,000 total samples. We observe greater changes occurring on the human lineage than mouse, and substantial regional variation that highlights cerebral cortex as the most diverged region. Glia, notably microglia, astrocytes, and oligodendrocytes are the most divergent cell type, three times more on average than neurons. We show that cis-regulatory sequence divergence explains a significant fraction of co-expression divergence. Moreover, protein coding sequence constraint parallels co-expression conservation, such that genes with loss of function intolerance are enriched in neuronal, rather than glial modules. We identify dozens of human neuropsychiatric and neurodegenerative disease risk genes, such as COMT, PSEN-1, LRRK2, SHANK3, and SNCA, with highly divergent co-expression between mouse and human and show that 3D human brain organoids recapitulate in vivo co-expression modules representing several human cell types.

Conclusions: We identify robust co-expression modules reflecting whole-brain and regional patterns of gene expression. Compared with those that represent basic metabolic processes, cell-type-specific modules, most prominently glial modules, are the most divergent between species. These data and analyses serve as a foundational resource to guide human disease modeling and its interpretation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-020-02257-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844938PMC
January 2021

p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).

Cell 2021 02 21;184(3):689-708.e20. Epub 2021 Jan 21.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886018PMC
February 2021

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates.

Biol Psychiatry 2021 05 2;89(9):896-910. Epub 2020 Nov 2.

Department of Psychiatry, Center for Autism Research and Treatment, Los Angeles, California; Program in Neurobehavioral Genetics, Center for Autism Research and Treatment, Los Angeles, California; Department of Neurology, Center for Autism Research and Treatment, Los Angeles, California; Department of Human Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address:

Background: Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates.

Methods: We performed RNA sequencing across psychiatrically relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus) and primary visual cortex for comparison from 3.5- to 4-year-old male MIA-exposed and control offspring-an age comparable to mid adolescence in humans.

Results: We identify 266 unique genes differentially expressed in at least one brain region, with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Although we observed temporal and regional differences, transcriptomic changes were shared across first- and second-trimester exposures, including for the top differentially expressed genes-PIWIL2 and MGARP. In addition to PIWIL2, several other regulators of retrotransposition and endogenous transposable elements were dysregulated following MIA, potentially connecting MIA to retrotransposition.

Conclusions: Together, these results begin to elucidate the brain-level molecular processes through which MIA may impart risk for psychiatric disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052273PMC
May 2021

Polygenicity in Psychiatry-Like It or Not, We Have to Understand It.

Biol Psychiatry 2021 01;89(1):2-4

Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Center for Autism Research and Treatment, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2020.10.002DOI Listing
January 2021

Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement.

Elife 2020 12 2;9. Epub 2020 Dec 2.

Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.

Sciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6C monocytes infiltrate the nerve first and rapidly give way to Ly6C inflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages 'eat' apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF-deficient () mice, inflammation resolution is delayed and conditioning-lesion-induced regeneration of DRG neuron central axons is abolished. Thus, carefully orchestrated inflammation resolution in the nerve is required for conditioning-lesion-induced neurorepair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.60223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735761PMC
December 2020

Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression.

Cell Rep 2020 11;33(7):108398

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

To understand how neural-immune-associated genes and pathways contribute to neurodegenerative disease pathophysiology, we performed a systematic functional genomic analysis in purified microglia and bulk tissue from mouse and human AD, FTD, and PSP. We uncover a complex temporal trajectory of microglial-immune pathways involving the type 1 interferon response associated with tau pathology in the early stages, followed by later signatures of partial immune suppression and, subsequently, the type 2 interferon response. We find that genetic risk for dementias shows disease-specific patterns of pathway enrichment. We identify drivers of two gene co-expression modules conserved from mouse to human, representing competing arms of microglial-immune activation (NAct) and suppression (NSupp) in neurodegeneration. We validate our findings by using chemogenetics, experimental perturbation data, and single-cell sequencing in post-mortem brains. Our results refine the understanding of stage- and disease-specific microglial responses, implicate microglial viral defense pathways in dementia pathophysiology, and highlight therapeutic windows.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.108398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842189PMC
November 2020

Editorial overview: Neurodevelopment Diseases and Neurogenetics pivot towards mechanisms and therapies.

Curr Opin Genet Dev 2020 12 8;65:iii-vii. Epub 2020 Nov 8.

Rady Children's Institute for Genomic Medicine, Departments of Neuroscience and Pediatrics, University of California, San Diego, United States. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gde.2020.09.001DOI Listing
December 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

Microglia-organized scar-free spinal cord repair in neonatal mice.

Nature 2020 11 7;587(7835):613-618. Epub 2020 Oct 7.

F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.

Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2795-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704837PMC
November 2020

Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.

Nat Med 2020 12 28;26(12):1888-1898. Epub 2020 Sep 28.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.

22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1043-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525897PMC
December 2020
-->