Publications by authors named "Schahram Akbarian"

146 Publications

Comprehensive identification of somatic nucleotide variants in human brain tissue.

Genome Biol 2021 Mar 29;22(1):92. Epub 2021 Mar 29.

Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.

Background: Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.

Results: Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.

Conclusions: This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.
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http://dx.doi.org/10.1186/s13059-021-02285-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006362PMC
March 2021

Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection.

Stem Cell Reports 2021 03 13;16(3):505-518. Epub 2021 Feb 13.

Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant interindividual variability. In addition to showing more disease in males, the elderly, and individuals with underlying comorbidities, SARS-CoV-2 can seemingly afflict healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants influence vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single-nucleotide polymorphism (rs4702), common in the population and located in the 3' UTR of the protease FURIN, influences alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can have an impact on viral infection and thus contribute to clinical heterogeneity in COVID-19. Ongoing genetic studies will help to identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs.
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http://dx.doi.org/10.1016/j.stemcr.2021.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881728PMC
March 2021

Parsing the Functional Impact of Noncoding Genetic Variants in the Brain Epigenome.

Biol Psychiatry 2021 Jan 3;89(1):65-75. Epub 2020 Oct 3.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

The heritability of common psychiatric disorders has motivated global efforts to identify risk-associated genetic variants and elucidate molecular pathways connecting DNA sequence to disease-associated brain dysfunction. The overrepresentation of risk variants among gene regulatory loci instead of protein-coding loci, however, poses a unique challenge in discerning which among the many thousands of variants identified contribute functionally to disease etiology. Defined broadly, psychiatric epigenomics seeks to understand the effects of disease-associated genetic variation on functional readouts of chromatin in an effort to prioritize variants in terms of their impact on gene expression in the brain. Here, we provide an overview of epigenomic mapping in the human brain and highlight findings of particular relevance to psychiatric genetics. Computational methods, including convolutional neuronal networks, and other machine learning approaches hold great promise for elucidating the functional impact of both common and rare genetic variants, thereby refining the epigenomic architecture of psychiatric disorders and enabling integrative analyses of regulatory noncoding variants in the context of large population-level genome and phenome databases.
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http://dx.doi.org/10.1016/j.biopsych.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718420PMC
January 2021

Common genetic variation in humans impacts susceptibility to SARS-CoV-2 infection.

bioRxiv 2020 Sep 21. Epub 2020 Sep 21.

Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying co-morbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants also impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population at large, and located in the 3'UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 . Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in SARS-CoV-2. Ongoing genetic studies will help to better identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs that might treat disease.
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http://dx.doi.org/10.1101/2020.09.20.300574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523109PMC
September 2020

A prefrontal-paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice.

Nat Neurosci 2020 10 31;23(10):1240-1252. Epub 2020 Aug 31.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA.

Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.
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http://dx.doi.org/10.1038/s41593-020-0695-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898783PMC
October 2020

Genotype-phenotype correlation at codon 1740 of SETD2.

Am J Med Genet A 2020 09 24;182(9):2037-2048. Epub 2020 Jul 24.

Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, New York, USA.

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.
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http://dx.doi.org/10.1002/ajmg.a.61724DOI Listing
September 2020

Epigenetic Clocks in Schizophrenia: Promising Biomarkers, Foggy Clockwork.

Biol Psychiatry 2020 08;88(3):210-211

Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.04.004DOI Listing
August 2020

Investigation of Schizophrenia with Human Induced Pluripotent Stem Cells.

Adv Neurobiol 2020 ;25:155-206

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Schizophrenia is a chronic and severe neuropsychiatric condition manifested by cognitive, emotional, affective, perceptual, and behavioral abnormalities. Despite decades of research, the biological substrates driving the signs and symptoms of the disorder remain elusive, thus hampering progress in the development of treatments aimed at disease etiologies. The recent emergence of human induced pluripotent stem cell (hiPSC)-based models has provided the field with a highly innovative approach to generate, study, and manipulate living neural tissue derived from patients, making possible the exploration of fundamental roles of genes and early-life stressors in disease-relevant cell types. Here, we begin with a brief overview of the clinical, epidemiological, and genetic aspects of the condition, with a focus on schizophrenia as a neurodevelopmental disorder. We then highlight relevant technical advancements in hiPSC models and assess novel findings attained using hiPSC-based approaches and their implications for disease biology and treatment innovation. We close with a critical appraisal of the developments necessary for both further expanding knowledge of schizophrenia and the translation of new insights into therapeutic innovations.
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http://dx.doi.org/10.1007/978-3-030-45493-7_6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033573PMC
November 2020

A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles.

Nat Neurosci 2020 04 9;23(4):583-593. Epub 2020 Mar 9.

UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.

Most risk variants for brain disorders identified by genome-wide association studies reside in the noncoding genome, which makes deciphering biological mechanisms difficult. A commonly used tool, multimarker analysis of genomic annotation (MAGMA), addresses this issue by aggregating single nucleotide polymorphism associations to nearest genes. Here we developed a platform, Hi-C-coupled MAGMA (H-MAGMA), that advances MAGMA by incorporating chromatin interaction profiles from human brain tissue across two developmental epochs and two brain cell types. By analyzing gene regulatory relationships in the disease-relevant tissue, H-MAGMA identified neurobiologically relevant target genes. We applied H-MAGMA to five psychiatric disorders and four neurodegenerative disorders to interrogate biological pathways, developmental windows and cell types implicated for each disorder. Psychiatric-disorder risk genes tended to be expressed during mid-gestation and in excitatory neurons, whereas neurodegenerative-disorder risk genes showed increasing expression over time and more diverse cell-type specificities. H-MAGMA adds to existing analytic frameworks to help identify the neurobiological principles of brain disorders.
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http://dx.doi.org/10.1038/s41593-020-0603-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131892PMC
April 2020

Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior.

Nat Commun 2020 02 21;11(1):1003. Epub 2020 Feb 21.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior.
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http://dx.doi.org/10.1038/s41467-020-14740-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035248PMC
February 2020

A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons.

Genome Med 2020 02 19;12(1):19. Epub 2020 Feb 19.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap.

Methods: We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring the MDN's "spatial genome," including chromosomal contact landscapes as a critical layer of cell type-specific epigenomic regulation. Low-input Hi-C protocols were applied to 5-10 × 10 dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain.

Results: The Hi-C-reconstructed MDN spatial genome revealed 11 "Euclidean hot spots" of clustered chromatin domains harboring risk sequences for SCZ and elevated BMI. Inter- and intra-chromosomal contacts interconnecting SCZ and BMI risk sequences showed massive enrichment for brain-specific expression quantitative trait loci (eQTL), with gene ontologies, regulatory motifs and proteomic interactions related to adipogenesis and lipid regulation, dopaminergic neurogenesis and neuronal connectivity, and reward- and addiction-related pathways.

Conclusions: We uncovered shared nuclear topographies of cognitive and metabolic risk variants. More broadly, our PsychENCODE sponsored Hi-C study offers a novel genomic approach for the study of psychiatric and medical co-morbidities constrained by limited overlap of their respective genetic risk architectures on the linear genome.
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http://dx.doi.org/10.1186/s13073-020-0715-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031924PMC
February 2020

Use of the epigenetic toolbox
to contextualize common variants associated with schizophrenia risk
.

Dialogues Clin Neurosci 2019 12;21(4):407-416

Department of Psychiatry; Friedman Brain Institute; Icahn School of Medicine at Mount Sinai, New York, NY, US.

Schizophrenia is a debilitating psychiatric disorder with a complex genetic architecture and limited understanding of its neuropathology, reflected by the lack of diagnostic measures and effective pharmacological treatments. Geneticists have recently identified more than 145 risk loci comprising hundreds of common variants of small effect sizes, most of which lie in noncoding genomic regions. This review will discuss how the epigenetic toolbox can be applied to contextualize genetic findings in schizophrenia. Progress in next-generation sequencing, along with increasing methodological complexity, has led to the compilation of genome-wide maps of DNA methylation, histone modifications, RNA expression, and more. Integration of chromatin conformation datasets is one of the latest efforts in deciphering schizophrenia risk, allowing the identification of genes in contact with regulatory variants across 100s of kilobases. Large-scale multiomics studies will facilitate the prioritization of putative causal risk variants and gene networks that contribute to schizophrenia etiology, informing clinical diagnostics and treatment downstream.
.
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http://dx.doi.org/10.31887/DCNS.2019.21.4/sakbarianDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952750PMC
December 2019

Special volume: The genomics and epigenomics of schizophrenia.

Schizophr Res 2020 03 5;217:1-3. Epub 2019 Dec 5.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.schres.2019.11.056DOI Listing
March 2020

Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia.

Transl Psychiatry 2019 10 17;9(1):256. Epub 2019 Oct 17.

Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.

Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly located HLA-DRB5 and BTNL2 genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterized LINC01115 gene and recently identified BNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia.
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http://dx.doi.org/10.1038/s41398-019-0596-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797775PMC
October 2019

CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.

Sci Data 2019 09 24;6(1):180. Epub 2019 Sep 24.

Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .
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http://dx.doi.org/10.1038/s41597-019-0183-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760149PMC
September 2019

In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene.

Nat Commun 2019 09 11;10(1):4112. Epub 2019 Sep 11.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46 mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain's connectome via gene-targeted designer activators and repressor proteins.
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http://dx.doi.org/10.1038/s41467-019-12013-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739341PMC
September 2019

CRISPR-based functional evaluation of schizophrenia risk variants.

Schizophr Res 2020 03 3;217:26-36. Epub 2019 Jul 3.

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America. Electronic address:

As expanding genetic and genomic studies continue to implicate a growing list of variants contributing risk to neuropsychiatric disease, an important next step is to understand the functional impact and points of convergence of these risk factors. Here, with a focus on schizophrenia, we survey the most recent findings of the rare and common variants underlying genetic risk for schizophrenia. We discuss the ongoing efforts to validate these variants in post-mortem brain tissue, as well as new approaches to combine CRISPR-based genome engineering with patient-specific human induced pluripotent stem cell (hiPSC)-based models, in order to identify putative causal schizophrenia loci that regulate gene expression and cellular function. We consider the current limitations of hiPSC-based approaches as well as the future advances necessary to improve the fidelity of this human model. With the objective of utilizing patient genotype data to improve diagnosis and predict treatment response, the integration of CRISPR-genome engineering and hiPSC-based models represent an important strategy with which to systematically demonstrate the cell-type-specific effects of schizophrenia-associated variants.
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http://dx.doi.org/10.1016/j.schres.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939156PMC
March 2020

Metabolome signature of autism in the human prefrontal cortex.

Commun Biol 2019 21;2:234. Epub 2019 Jun 21.

1Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and Technology, Moscow, 121205 Russia.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with yet incompletely uncovered molecular determinants. Alterations in the abundance of low molecular weight compounds (metabolites) in ASD could add to our understanding of the disease. Indeed, such alterations take place in the urine, plasma and cerebellum of ASD individuals. In this work, we investigated mass-spectrometric signal intensities of 1,366 metabolites in the prefrontal cortex grey matter of 32 ASD and 40 control individuals. 15% of these metabolites showed significantly different intensities in ASD and clustered in 16 metabolic pathways. Of them, ten pathways were altered in urine and blood of ASD individuals (Fisher test,  < 0.05), opening an opportunity for the design of new diagnostic instruments. Furthermore, metabolic measurements conducted in 40 chimpanzees and 40 macaques showed an excess of metabolite intensity differences unique to humans, supporting the hypothesized disruption of evolutionary novel cortical mechanisms in ASD.
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http://dx.doi.org/10.1038/s42003-019-0485-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588695PMC
April 2020

Spatial genome exploration in the context of cognitive and neurological disease.

Curr Opin Neurobiol 2019 12 27;59:112-119. Epub 2019 Jun 27.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

The 'non-linear' genome, or the spatial proximity of non-contiguous sequences, emerges as an important regulatory layer for genome organization and function, including transcriptional regulation. Here, we review recent genome-scale chromosome conformation mappings ('Hi-C') in developing and adult human and mouse brain. Neural differentiation is associated with widespread remodeling of the chromosomal contact map, reflecting dynamic changes in cell-type-specific gene expression programs, with a massive (estimated 20-50%) net loss of chromosomal contacts that is specific for the neuronal lineage. Hi-C datasets provided an unexpected link between locus-specific abnormal expansion of repeat sequences positioned at the boundaries of self-associating topological chromatin domains, and monogenic neurodevelopmental and neurodegenerative disease. Furthermore, integrative cell-type-specific Hi-C and transcriptomic analysis uncovered an expanded genomic risk space for sequences conferring liability for schizophrenia and other cognitive disease. We predict that spatial genome exploration will deliver radically new insights into the brain nucleome in health and disease.
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http://dx.doi.org/10.1016/j.conb.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889018PMC
December 2019

Epigenetic-genetic chromatin footprinting identifies novel and subject-specific genes active in prefrontal cortex neurons.

FASEB J 2019 07 10;33(7):8161-8173. Epub 2019 Apr 10.

Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Human prefrontal cortex (PFC) is associated with broad individual variabilities in functions linked to personality, social behaviors, and cognitive functions. The phenotype variabilities associated with brain functions can be caused by genetic or epigenetic factors. The interactions between these factors in human subjects is, as of yet, poorly understood. The heterogeneity of cerebral tissue, consisting of neuronal and nonneuronal cells, complicates the comparative analysis of gene activities in brain specimens. To approach the underlying neurogenomic determinants, we performed a deep analysis of open chromatin-associated histone methylation in PFC neurons sorted from multiple human individuals in conjunction with whole-genome and transcriptome sequencing. Integrative analyses produced novel unannotated neuronal genes and revealed individual-specific chromatin "blueprints" of neurons that, in part, relate to genetic background. Surprisingly, we observed gender-dependent epigenetic signals, implying that gender may contribute to the chromatin variabilities in neurons. Finally, we found epigenetic, allele-specific activation of the testis-specific gene nucleoporin 210 like () in brain in some individuals, which we link to a genetic variant occurring in <3% of the human population. Recently, the locus has been associated with intelligence and mathematics ability. Our findings highlight the significance of epigenetic-genetic footprinting for exploring neurologic function in a subject-specific manner.-Gusev, F. E., Reshetov, D. A., Mitchell, A. C., Andreeva, T. V., Dincer, A., Grigorenko, A. P., Fedonin, G., Halene, T., Aliseychik, M., Goltsov, A. Y., Solovyev, V., Brizgalov, L., Filippova, E., Weng, Z., Akbarian, S., Rogaev, E. I. Epigenetic-genetic chromatin footprinting identifies novel and subject-specific genes active in prefrontal cortex neurons.
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http://dx.doi.org/10.1096/fj.201802646RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593885PMC
July 2019

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

Science 2018 12;362(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 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.
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http://dx.doi.org/10.1126/science.aat8464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413328PMC
December 2018

Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk.

Science 2018 12;362(6420)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10027, USA.

To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type-specific disease risk vulnerabilities in spatial genome organization.
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http://dx.doi.org/10.1126/science.aat4311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408958PMC
December 2018

Lipidome alterations in human prefrontal cortex during development, aging, and cognitive disorders.

Mol Psychiatry 2020 11 8;25(11):2952-2969. Epub 2018 Aug 8.

Skolkovo Institute of Science and Technology, Moscow, 143028, Russia.

Lipids are essential to brain functions, yet they remain largely unexplored. Here we investigated the lipidome composition of prefrontal cortex gray matter in 396 cognitively healthy individuals with ages spanning 100 years, as well as 67 adult individuals diagnosed with autism (ASD), schizophrenia (SZ), and Down syndrome (DS). Of the 5024 detected lipids, 95% showed significant age-dependent concentration differences clustering into four temporal stages, and resulting in a gradual increase in membrane fluidity in individuals ranging from newborn to nonagenarian. Aging affects 14% of the brain lipidome with late-life changes starting predominantly at 50-55 years of age-a period of general metabolic transition. All three diseases alter the brain lipidome composition, leading-among other things-to a concentration decrease in glycerophospholipid metabolism and endocannabinoid signaling pathways. Lipid concentration decreases in SZ were further linked to genetic variants associated with disease, indicating the relevance of the lipidome changes to disease progression.
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http://dx.doi.org/10.1038/s41380-018-0200-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577858PMC
November 2020

Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia.

Nat Commun 2018 08 7;9(1):3121. Epub 2018 Aug 7.

Center for Genomic and Computational Biology, Duke University, Durham, NC, 27708, USA.

Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in the brain are highly enriched for schizophrenia SNP heritability. Accessible chromatin regions that overlap evolutionarily conserved regions exhibit an even higher heritability enrichment, indicating that sequence conservation can further refine functional risk variants. We identify few differences in chromatin accessibility between cases and controls, in contrast to thousands of age-related differential accessible chromatin regions. Altogether, we characterize chromatin accessibility in the human prefrontal cortex, the effect of schizophrenia and age on chromatin accessibility, and provide evidence that our dataset will allow for fine mapping of risk variants.
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http://dx.doi.org/10.1038/s41467-018-05379-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081462PMC
August 2018

Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome.

Nat Neurosci 2018 08 23;21(8):1126-1136. Epub 2018 Jul 23.

Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.
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http://dx.doi.org/10.1038/s41593-018-0187-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063773PMC
August 2018

Chromosomal Conformations and Epigenomic Regulation in Schizophrenia.

Prog Mol Biol Transl Sci 2018 30;157:21-40. Epub 2018 Mar 30.

Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Chromosomal conformations, including promoter-enhancer loops, provide a critical regulatory layer for the transcriptional machinery. Therefore, schizophrenia, a common psychiatric disorder associated with broad changes in neuronal gene expression in prefrontal cortex and other brain regions implicated in psychosis, could be associated with alterations in higher-order chromatin. Here, we review early studies on spatial genome organization in the schizophrenia postmortem brain and discuss how integrative approaches using cell culture and animal model systems could gain deeper insight into the potential roles of higher-order chromatin for the neurobiology of and novel treatment avenues for common psychiatric disease.
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http://dx.doi.org/10.1016/bs.pmbts.2017.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318347PMC
March 2019

Activity-Induced Regulation of Synaptic Strength through the Chromatin Reader L3mbtl1.

Cell Rep 2018 06;23(11):3209-3222

Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA. Electronic address:

Homeostatic synaptic downscaling reduces neuronal excitability by modulating the number of postsynaptic receptors. Histone modifications and the subsequent chromatin remodeling play critical roles in activity-dependent gene expression. Histone modification codes are recognized by chromatin readers that affect gene expression by altering chromatin structure. We show that L3mbtl1 (lethal 3 malignant brain tumor-like 1), a polycomb chromatin reader, is downregulated by neuronal activity and is essential for synaptic response and downscaling. Genome-scale mapping of L3mbtl1 occupancies identified Ctnnb1 as a key gene downstream of L3mbtl1. Importantly, the occupancy of L3mbtl1 on the Ctnnb1 gene was regulated by neuronal activity. L3mbtl1 knockout neurons exhibited reduced Ctnnb1 expression. Partial knockdown of Ctnnb1 in wild-type neurons reduced excitatory synaptic transmission and abolished homeostatic downscaling, and transfecting Ctnnb1 in L3mbtl1 knockout neurons enhanced synaptic transmission and restored homeostatic downscaling. These results highlight a role for L3mbtl1 in regulating homeostasis of synaptic efficacy.
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http://dx.doi.org/10.1016/j.celrep.2018.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309677PMC
June 2018

Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS.

Am J Hum Genet 2018 06 24;102(6):1169-1184. Epub 2018 May 24.

Systems Biology, Sage Bionetworks, Seattle, WA 98109, USA. Electronic address:

Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993513PMC
June 2018

Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.

Front Pediatr 2018 3;6:82. Epub 2018 Apr 3.

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Human-induced pluripotent stem cells (hiPSCs) have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional "mini-brains" and clustered, regularly interspersed short palindromic repeats (CRISPR)-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson's disease, and consider the future of this groundbreaking research.
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http://dx.doi.org/10.3389/fped.2018.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891587PMC
April 2018

Allele-specific expression in a family quartet with autism reveals mono-to-biallelic switch and novel transcriptional processes of autism susceptibility genes.

Sci Rep 2018 03 9;8(1):4277. Epub 2018 Mar 9.

Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is unknown. Dysregulated allele-specific expression (ASE) has been identified in persons with ASD; however, a comprehensive analysis of ASE has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE using genomic DNA from parent and offspring and RNA from offspring's postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing revealed distinct ASE patterns from the PFC of both offspring. However, only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP and ZNF407. We also identified a novel site of RNA-editing in KMT2C in addition to new monoallelically-expressed genes and miRNAs. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights into the pathogenesis of ASD.
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http://dx.doi.org/10.1038/s41598-018-22753-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844893PMC
March 2018