Publications by authors named "Daniel R Weinberger"

442 Publications

Genome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk.

Nat Commun 2021 09 2;12(1):5251. Epub 2021 Sep 2.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

DNA methylation (DNAm) is an epigenetic regulator of gene expression and a hallmark of gene-environment interaction. Using whole-genome bisulfite sequencing, we have surveyed DNAm in 344 samples of human postmortem brain tissue from neurotypical subjects and individuals with schizophrenia. We identify genetic influence on local methylation levels throughout the genome, both at CpG sites and CpH sites, with 86% of SNPs and 55% of CpGs being part of methylation quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by a given SNP, highlighting the genes and regions with which these loci are epigenetically associated. These findings can be used to better characterize schizophrenia GWAS-identified variants as epigenetic risk variants. Regions differentially methylated by schizophrenia risk-SNPs explain much of the heritability associated with risk loci, despite covering only a fraction of the genomic space. We provide a comprehensive, single base resolution view of association between genetic variation and genomic methylation, and implicate schizophrenia GWAS-associated variants as influencing the epigenetic plasticity of the brain.
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http://dx.doi.org/10.1038/s41467-021-25517-3DOI Listing
September 2021

Replicating G × E: The Devil and the Details.

Schizophr Bull 2021 Sep 2. Epub 2021 Sep 2.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

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http://dx.doi.org/10.1093/schbul/sbab109DOI Listing
September 2021

Induced Pluripotent Stem Cells in Psychiatry: An Overview and Critical Perspective.

Biol Psychiatry 2021 Sep 21;90(6):362-372. Epub 2021 Apr 21.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom; Oxford Health NHS Foundation Trust, Oxford, United Kingdom. Electronic address:

A key challenge in psychiatry research is the development of high-fidelity model systems that can be experimentally manipulated to explore and test pathophysiological mechanisms of illness. In this respect, the emerging capacity to derive neural cells and circuits from human induced pluripotent stem cells (iPSCs) has generated significant excitement. This review aims to provide a critical appraisal of the potential for iPSCs in illuminating pathophysiological mechanisms in the context of other available technical approaches. We discuss the selection of iPSC phenotypes relevant to psychiatry, the information that researchers can draw on to help guide these decisions, and how researchers choose between the use of 2-dimensional cultures and the use of more complex 3-dimensional model systems. We discuss the strengths and limitations of current models and the challenges and opportunities that they present. Finally, we discuss the potential of iPSC-based model systems for clarifying the mechanisms underlying genetic risk for psychiatry and the steps that will be needed to ensure that robust and reliable conclusions can be drawn. We argue that while iPSC-based models are ideally placed to study fundamental processes occurring within and between neural cells, they are often less well suited for case-control studies, given issues relating to statistical power and the challenges in identifying which cellular phenotypes are meaningful at the level of the whole individual. Our aim is to highlight the importance of considering the hypotheses of a given study to guide decisions about which, if any, iPSC-based system is most appropriate to address it.
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http://dx.doi.org/10.1016/j.biopsych.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375580PMC
September 2021

A generative-discriminative framework that integrates imaging, genetic, and diagnosis into coupled low dimensional space.

Neuroimage 2021 09 10;238:118200. Epub 2021 Jun 10.

Department of Electrical and Computer Engineering, Johns Hopkins University, USA.

We propose a novel optimization framework that integrates imaging and genetics data for simultaneous biomarker identification and disease classification. The generative component of our model uses a dictionary learning framework to project the imaging and genetic data into a shared low dimensional space. We have coupled both the data modalities by tying the linear projection coefficients to the same latent space. The discriminative component of our model uses logistic regression on the projection vectors for disease diagnosis. This prediction task implicitly guides our framework to find interpretable biomarkers that are substantially different between a healthy and disease population. We exploit the interconnectedness of different brain regions by incorporating a graph regularization penalty into the joint objective function. We also use a group sparsity penalty to find a representative set of genetic basis vectors that span a low dimensional space where subjects are easily separable between patients and controls. We have evaluated our model on a population study of schizophrenia that includes two task fMRI paradigms and single nucleotide polymorphism (SNP) data. Using ten-fold cross validation, we compare our generative-discriminative framework with canonical correlation analysis (CCA) of imaging and genetics data, parallel independent component analysis (pICA) of imaging and genetics data, random forest (RF) classification, and a linear support vector machine (SVM). We also quantify the reproducibility of the imaging and genetics biomarkers via subsampling. Our framework achieves higher class prediction accuracy and identifies robust biomarkers. Moreover, the implicated brain regions and genetic variants underlie the well documented deficits in schizophrenia.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118200DOI Listing
September 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

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

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Developmental Profile of Psychiatric Risk Associated With Voltage-Gated Cation Channel Activity.

Biol Psychiatry 2021 Sep 13;90(6):399-408. Epub 2021 Mar 13.

Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Background: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant.

Methods: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage.

Results: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes.

Conclusions: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
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http://dx.doi.org/10.1016/j.biopsych.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375582PMC
September 2021

Comprehensive identification of somatic nucleotide variants in human brain tissue.

Genome Biol 2021 03 29;22(1):92. Epub 2021 Mar 29.

Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, 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

Genome-wide analyses of smoking behaviors in schizophrenia: Findings from the Psychiatric Genomics Consortium.

J Psychiatr Res 2021 05 18;137:215-224. Epub 2021 Feb 18.

Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY, USA. Electronic address:

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (r = 0.159; P = 5.05 × 10), cigarettes-smoked-per-day (r = 0.094; P = 0.006), and age-of-onset of smoking (r = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (r = 0.624, P = 0.002) and cigarettes-smoked-per-day (r = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096167PMC
May 2021

Single molecule in situ hybridization reveals distinct localizations of schizophrenia risk-related transcripts SNX19 and AS3MT in human brain.

Mol Psychiatry 2021 Mar 1. Epub 2021 Mar 1.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with schizophrenia risk. Integration of RNA-sequencing data from postmortem human brains with these risk SNPs identified transcripts associated with increased schizophrenia susceptibility, including a class of exon 9-spliced isoforms of Sorting nexin-19 (SNX19) and an isoform of Arsenic methyltransferase (AS3MT) splicing out exons 2 and 3 (AS3MT). However, the biological function of these transcript variants is unclear. Defining the cell types where these risk transcripts are dominantly expressed is an important step to understand function, in prioritizing specific cell types and/or neural pathways in subsequent studies. To identify the cell type-specific localization of SNX19 and AS3MT in the human dorsolateral prefrontal cortex (DLPFC), we used single-molecule in situ hybridization techniques combined with automated quantification and machine learning approaches to analyze 10 postmortem brains of neurotypical individuals. These analyses revealed that both pan-SNX19 and pan-AS3MT were more highly expressed in neurons than non-neurons in layers II/III and VI of DLPFC. Furthermore, pan-SNX19 was preferentially expressed in glutamatergic neurons, while pan-AS3MT was preferentially expressed in GABAergic neurons. Finally, we utilized duplex BaseScope technology, to delineate the localization of SNX19 and AS3MT splice variants, revealing consistent trends in spatial gene expression among pan-transcripts and schizophrenia risk-related transcript variants. These findings demonstrate that schizophrenia risk transcripts have distinct localization patterns in the healthy human brains, and suggest that SNX19 transcripts might disrupt the normal function of glutamatergic neurons, while AS3MT may lead to disturbances in the GABAergic system in the pathophysiology of schizophrenia.
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http://dx.doi.org/10.1038/s41380-021-01046-9DOI Listing
March 2021

Placental genomic risk scores and early neurodevelopmental outcomes.

Proc Natl Acad Sci U S A 2021 02;118(7)

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205;

Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.
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http://dx.doi.org/10.1073/pnas.2019789118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896349PMC
February 2021

Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition.

Am J Psychiatry 2020 12;177(12):1129-1139

Baltimore Research and Education Foundation, Baltimore (Zink); Lieber Institute for Brain Development, Baltimore (Zink, Weinberger, Quillian, Ulrich, Chen, Jaffe, Kleinman, Hyde, Prettyman, Giegerich, Carta, van Ginkel, Bigos); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Zink, Sawa, Weinberger, Jaffe, Kleinman, Hyde, Bigos); Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore (Barker, Wang); Department of Oncology, Johns Hopkins School of Medicine, Baltimore (Barker); Kennedy Krieger Institute, Baltimore (Barker); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Sawa, Jaffe); Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger); McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Sawa, Weinberger, Jaffe); Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore (Sawa); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Weinberger, Hyde); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Center for Computational Biology, Johns Hopkins University, Baltimore (Jaffe); Department of Neuroscience, University of Pennsylvania, Philadelphia (Prettyman); Eating Disorders Center for Treatment and Research, University of California San Diego (Giegerich); Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore (Carta, van Ginkel, Bigos); and Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore (Bigos).

Objective: Altering the metabotropic glutamate receptor 3 (mGluR3) by pharmacology or genetics is associated with differences in learning and memory in animals and humans. GRM3 (the gene coding for mGluR3) is also genome-wide associated with risk for schizophrenia. The neurotransmitter -acetyl-aspartyl-glutamate (NAAG) is the selective endogenous agonist of mGluR3, and increasing NAAG may improve cognition. Glutamate carboxypeptidase II (GCPII), coded by the gene folate hydrolase 1 (FOLH1), regulates the amount of NAAG in the synapse. The goal of this study was to determine the relationship between FOLH1, NAAG levels, measures of human cognition, and neural activity associated with cognition.

Methods: The effects of genetic variation in FOLH1 on mRNA expression in human brain and NAAG levels using 7-T magnetic resonance spectroscopy (MRS) were measured. NAAG levels and FOLH1 genetic variation were correlated with measures of cognition in subjects with psychosis and unaffected subjects. Additionally, FOLH1 genetic variation was correlated with neural activity during working memory, as measured by functional MRI (fMRI).

Results: A missense mutation in FOLH1 (rs202676 G allele) was associated with increased FOLH1 mRNA in the dorsolateral prefrontal cortex of brains from unaffected subjects and schizophrenia patients. This FOLH1 variant was associated with decreased NAAG levels in unaffected subjects and patients with psychosis. NAAG levels were positively correlated with visual memory performance. Carriers of the FOLH1 variant associated with lower NAAG levels had lower IQ scores. Carriers of this FOLH1 variant had less efficient cortical activity during working memory.

Conclusions: These data show that higher NAAG levels are associated with better cognition, suggesting that increasing NAAG levels through FOLH1/GCPII inhibition may improve cognition. Additionally, NAAG levels measured by MRS and cortical efficiency during working memory measured by fMRI have the potential to be neuroimaging biomarkers for future clinical trials.
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http://dx.doi.org/10.1176/appi.ajp.2020.19111152DOI Listing
December 2020

Nimodipine improves cortical efficiency during working memory in healthy subjects.

Transl Psychiatry 2020 11 2;10(1):372. Epub 2020 Nov 2.

Lieber Institute for Brain Development, Baltimore, MD, United States.

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; P < 0.05; n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.
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http://dx.doi.org/10.1038/s41398-020-01066-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606375PMC
November 2020

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

Hum Brain Mapp 2020 Oct 7. Epub 2020 Oct 7.

Neuroscience Research Australia, Sydney, Australia.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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http://dx.doi.org/10.1002/hbm.25206DOI Listing
October 2020

Missing in Action: African Ancestry Brain Research.

Neuron 2020 08 24;107(3):407-411. Epub 2020 Jul 24.

Morgan State University, Provost and Senior Vice President for Academic Affairs, Professor of Engineering, Baltimore, MD 21251, USA.

Individuals of African ancestry have been starkly underrepresented in the pursuit of personalized medicine for brain illnesses. The African Ancestry Neuroscience Research Initiative will seek to generate much-needed brain gene and protein expression profiles for people of African ancestry.
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http://dx.doi.org/10.1016/j.neuron.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380218PMC
August 2020

Structural Magnetic Resonance Imaging All Over Again.

JAMA Psychiatry 2021 Jan;78(1):11-12

Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1001/jamapsychiatry.2020.1941DOI Listing
January 2021

Comment on Limbic Hyperactivity in Response to Emotionally Neutral Stimuli in Schizophrenia: A Neuroimaging Meta-Analysis of the Hypervigilant Mind.

Am J Psychiatry 2020 07;177(7):639-640

Department of Psychiatry, Medstar Georgetown University Hospital, Washington, DC (Rasetti); Lieber Institute for Brain Development and Maltz Research Laboratories, Baltimore (Chen, Weinberger); Department of Neurology, Department of Neuroscience, Department of Psychiatry and Behavioral Sciences, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore (Weinberger).

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http://dx.doi.org/10.1176/appi.ajp.2020.19090973DOI Listing
July 2020

Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex.

Epigenetics 2021 01 15;16(1):1-13. Epub 2020 Jul 15.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus , Baltimore, MD, USA.

DNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain is a highly dynamic tissue, but our understanding of key drivers of epigenetic variability across development is limited. We, therefore, assessed genomic methylation at over 39 million sites in the prenatal cortex using whole-genome bisulfite sequencing and found loci and regions in which methylation levels are dynamic across development. We saw that DNAm at these loci was associated with nearby gene expression and enriched for enhancer chromatin states in prenatal brain tissue. Additionally, these loci were enriched for genes associated with neuropsychiatric disorders and genes involved with neurogenesis. We also found autosomal differences in DNAm between the sexes during prenatal development, though these have less clear functional consequences. We lastly confirmed that the dynamic methylation at this critical period is specifically CpG methylation, with generally low levels of CpH methylation. Our findings provide detailed insight into prenatal brain development as well as clues to the pathogenesis of psychiatric traits seen later in life.
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http://dx.doi.org/10.1080/15592294.2020.1786304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889237PMC
January 2021

A glioneuronal tumor with fusion.

NPJ Genom Med 2020 3;5:24. Epub 2020 Jun 3.

Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, 03080 Korea.

We report a case of glioneuronal tumor (GNT) with a discovery of novel gene fusion of resulting from aberrant chromosome 7 abnormalities. We executed an elaborate genomic study on this case including whole-exome sequencing and RNA sequencing. Genomic analysis of the tumor revealed aberrations in chromosomes 1 and 7 and a fusion. Further analysis of the upregulated genes revealed substantial connections with MAPK pathway activation. We concluded that the chromosome 7 abnormalities prompted gene fusion which successively leads to MAPK pathway activation. We deliberated that MAPK pathway activation is one of the driver pathways responsible for the oncogenesis of GNT.
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http://dx.doi.org/10.1038/s41525-020-0131-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270112PMC
June 2020

Parietal-Prefrontal Feedforward Connectivity in Association With Schizophrenia Genetic Risk and Delusions.

Am J Psychiatry 2020 12 27;177(12):1151-1158. Epub 2020 May 27.

Lieber Institute for Brain Development, Baltimore (Greenman, La, Shah, Chen, Weinberger, Tan); Clinical and Translational Neuroscience Branch, Section on Integrative Neuroimaging, Psychosis and Cognitive Studies Section, NIMH Intramural Research Program, Bethesda, Md. (Berman); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore (Weinberger, Tan); Departments of Neurology and Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Weinberger).

Objective: Conceptualizations of delusion formation implicate deficits in feedforward information updating across the posterior to prefrontal cortices, resulting in dysfunctional integration of new information about contexts in working memory and, ultimately, failure to update overfamiliar prior beliefs. The authors used functional MRI and machine learning models to address individual variability in feedforward parietal-prefrontal information updating in patients with schizophrenia. They examined relationships between feedforward connectivity, and delusional thinking and polygenic risk for schizophrenia.

Methods: The authors studied 66 schizophrenia patients and 143 healthy control subjects during performance of context updating in working memory. Dynamic causal models of effective connectivity were focused on regions of the prefrontal and parietal cortex potentially implicated in delusion processes. The effect of polygenic risk for schizophrenia on connectivity was examined in healthy individuals. The authors then leveraged support vector regression models to define optimal normalized target connectivity tailored for each patient and tested the extent to which deviation from this target could predict individual variation in severity of delusions.

Results: In schizophrenia patients, updating and manipulating context information was disproportionately less accurate than was working memory maintenance, with an interaction of task accuracy by diagnosis. Patients with delusions also tended to have relatively reduced parietal-prefrontal feedforward effective connectivity during context updating in working memory manipulation. The same connectivity was adversely influenced by polygenic risk for schizophrenia in healthy subjects. Individual patients' deviation from predicted "normal" feedforward connectivity based on the support vector regression models correlated with severity of delusions.

Conclusions: These computationally derived observations support a role for feedforward parietal-prefrontal information processing deficits in delusional psychopathology and in genetic risk for schizophrenia.
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http://dx.doi.org/10.1176/appi.ajp.2020.19111176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704895PMC
December 2020

Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia.

Transl Psychiatry 2020 05 19;10(1):158. Epub 2020 May 19.

The Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA.

Beyond being one the most widely used psychoactive drugs in the world, cannabis has been identified as an environmental risk factor for psychosis. Though the relationship between cannabis use and psychiatric disorders remains controversial, consistent association between early adolescent cannabis use and the subsequent risk of psychosis suggested adolescence may be a particularly vulnerable period. Previous findings on gene by environment interactions indicated that cannabis use may only increase the risk for psychosis in the subjects who have a specific genetic vulnerability. The type 1 cannabinoid receptor (CB1), encoded by the CNR1 gene, is a key component of the endocannabinoid system. As the primary endocannabinoid receptor in the brain, CB1 is the main molecular target of the endocannabinoid ligand, as well as tetrahydrocannabinol (THC), the principal psychoactive ingredient of cannabis. In this study, we have examined mRNA expression and DNA methylation of CNR1 in human prefrontal cortex (PFC), hippocampus, and caudate samples. The expression of CNR1 is higher in fetal PFC and hippocampus, then drops down dramatically after birth. The lifespan trajectory of CNR1 expression in the DLPFC differentially correlated with age by allelic variation at rs4680, a functional polymorphism in the COMT gene. Compared with COMT methionine carriers, Caucasian carriers of the COMT valine allele have a stronger negative correlation between the expression of CNR1 in DLPFC and age. In contrast, the methylation level of cg02498983, which is negatively correlated with the expression of CNR1 in PFC, showed the strongest positive correlation with age in PFC of Caucasian carriers of COMT valine. Additionally, we have observed decreased mRNA expression of CNR1 in the DLPFC of patients with schizophrenia. Further analysis revealed a positive eQTL SNP, rs806368, which predicted the expression of a novel transcript of CNR1 in human DLPFC, hippocampus and caudate. This SNP has been associated with addiction and other psychiatric disorders. THC or ethanol are each significantly associated with dysregulated expression of CNR1 in the PFC of patients with affective disorder, and the expression of CNR1 is significantly upregulated in the PFC of schizophrenia patients who completed suicide. Our results support previous studies that have implicated the endocannabinoid system in the pathology of schizophrenia and provided additional insight into the mechanism of increasing risk for schizophrenia in the adolescent cannabis users.
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http://dx.doi.org/10.1038/s41398-020-0832-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237456PMC
May 2020

Special Article: Translational Science Update. Pharmacological Implications of Emerging Schizophrenia Genetics: Can the Bridge From 'Genomics' to 'Therapeutics' be Defined and Traversed?

J Clin Psychopharmacol 2020 Jul/Aug;40(4):323-329

Lieber Institute for Brain Development and the Departments of Psychiatry, Neurology, Neuroscience and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Recent schizophrenia genome-wide association studies (GWAS) have identified genomic variants of common and rare frequency, significantly associated with schizophrenia. While numerous functional genomics efforts are ongoing to elucidate the biological effects of schizophrenia risk variants, a consideration of their therapeutic implications is timely and imperative, for patients as well as for an iterative effect on elucidating the underlying biology and pathophysiology of illness. The current article reviews efforts to translate emerging schizophrenia genomics into novel approaches to target discovery and therapeutic intervention. Though the path from 'genetic risk to therapy' is far from straightforward, there are provocative early possibilities that harbor the promise of treatment based on causation rather than phenomenology, as well as 'precision psychiatry,' a basis for stratifying patients to enable more precise and effective, personalized therapy.
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http://dx.doi.org/10.1097/JCP.0000000000001215DOI Listing
January 2021

Cortical cellular diversity and development in schizophrenia.

Mol Psychiatry 2021 01 13;26(1):203-217. Epub 2020 May 13.

Lieber Institute for Brain Development, Baltimore, MD, USA.

While a definitive understanding of schizophrenia etiology is far from current reality, an increasing body of evidence implicates perturbations in early development that alter the trajectory of brain maturation in this disorder, leading to abnormal function in early childhood and adulthood. This atypical development likely arises from an interaction of many brain cell types that follow distinct developmental paths. Because both cellular identity and development are governed by the transcriptome and epigenome, two levels of gene regulation that have the potential to reflect both genetic and environmental influences, mapping "omic" changes over development in diverse cells is a fruitful avenue for schizophrenia research. In this review, we provide a survey of human brain cellular composition and development, levels of genomic regulation that determine cellular identity and developmental trajectories, and what is known about how genomic regulation is dysregulated in specific cell types in schizophrenia. We also outline technical challenges and solutions to conducting cell type-specific functional genomic studies in human postmortem brain.
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http://dx.doi.org/10.1038/s41380-020-0775-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666011PMC
January 2021

Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates.

Cell Rep 2020 05;31(5):107599

Lieber Institute for Brain Development, 855 North Wolfe St., Baltimore, MD 21205, USA. Electronic address:

Better understanding of the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here, we use RNA sequencing, cell imaging, and lineage tracing of mouse and human in vitro NSCs and monkey brain sections to model the generation of cortical neuronal fates. We show that conserved signaling mechanisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons. As human telencephalic NSCs develop from pluripotency in vitro, they transition through organizer states that spatially pattern the cortex before generating glutamatergic precursor fates. NSCs derived from multiple human pluripotent lines vary in these early patterning states, leading differentially to dorsal or ventral telencephalic fates. This work furthers systematic analyses of the earliest patterning events that generate the major neuronal trajectories of the human telencephalon.
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http://dx.doi.org/10.1016/j.celrep.2020.107599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357345PMC
May 2020

Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk.

Nat Neurosci 2020 04 16;23(4):510-519. Epub 2020 Mar 16.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C. These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain.
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http://dx.doi.org/10.1038/s41593-020-0604-zDOI Listing
April 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Neural substrates of smoking and reward cue reactivity in smokers: a meta-analysis of fMRI studies.

Transl Psychiatry 2020 03 17;10(1):97. Epub 2020 Mar 17.

Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.

Smoking is partly attributed to alterations of reward processing. However, findings on the neurobiological mechanisms that underlie smoking-related and smoking-unrelated reward processing in smokers have been inconsistent. Neuroimaging experiments that used functional magnetic resonance imaging (fMRI) and reported brain responses to smoking-related cues and nonsmoking reward-related cues in smokers and healthy controls as coordinates in a standard anatomic reference space were identified by searching the PubMed, Embase, and Web of Science databases up to December 2018. Three meta-analyses were performed using random-effect nonparametric statistics with Seed-based d Mapping software, with brain activity contrast from individual studies as the input. The striatum showed higher activation in response to smoking-related cues compared with neutral cues in 816 smokers from 28 studies and lower activation in response to nonsmoking reward-related cues in 275 smokers compared with 271 healthy control individuals from 13 studies. The relative reactivity of the putamen to smoking-related cues increased in 108 smokers compared with 107 healthy controls from seven studies. Meta-regression showed that smokers with a greater severity of nicotine dependence exhibited less engagement of the striatum in response to both smoking-related cues and nonsmoking reward-related cues. The present results reveal the disruption of reward system function in smokers and provide new insights into diverging theories of addiction. With the escalation of nicotine dependence, nicotine appears to exert dynamic effects on reward processing, based on incentive sensitization theory and reward deficiency syndrome theory.
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http://dx.doi.org/10.1038/s41398-020-0775-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078287PMC
March 2020

Dissecting transcriptomic signatures of neuronal differentiation and maturation using iPSCs.

Nat Commun 2020 01 23;11(1):462. Epub 2020 Jan 23.

Clinical and Translational Neuroscience Branch, NIMH Intramural Research Program, Bethesda, MD, USA.

Human induced pluripotent stem cells (hiPSCs) are a powerful model of neural differentiation and maturation. We present a hiPSC transcriptomics resource on corticogenesis from 5 iPSC donor and 13 subclonal lines across 9 time points over 5 broad conditions: self-renewal, early neuronal differentiation, neural precursor cells (NPCs), assembled rosettes, and differentiated neuronal cells. We identify widespread changes in the expression of both individual features and global patterns of transcription. We next demonstrate that co-culturing human NPCs with rodent astrocytes results in mutually synergistic maturation, and that cell type-specific expression data can be extracted using only sequencing read alignments without cell sorting. We lastly adapt a previously generated RNA deconvolution approach to single-cell expression data to estimate the relative neuronal maturity of iPSC-derived neuronal cultures and human brain tissue. Using many public datasets, we demonstrate neuronal cultures are maturationally heterogeneous but contain subsets of neurons more mature than previously observed.
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http://dx.doi.org/10.1038/s41467-019-14266-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978526PMC
January 2020

Characterizing the nuclear and cytoplasmic transcriptomes in developing and mature human cortex uncovers new insight into psychiatric disease gene regulation.

Genome Res 2020 01 18;30(1):1-11. Epub 2019 Dec 18.

Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA.

Transcriptome compartmentalization by the nuclear membrane provides both stochastic and functional buffering of transcript activity in the cytoplasm, and has recently been implicated in neurodegenerative disease processes. Although many mechanisms regulating transcript compartmentalization are also prevalent in brain development, the extent to which subcellular localization differs as the brain matures has yet to be addressed. To characterize the nuclear and cytoplasmic transcriptomes during brain development, we sequenced both RNA fractions from homogenate prenatal and adult human postmortem cortex using poly(A)+ and Ribo-Zero library preparation methods. We find that while many genes are differentially expressed by fraction and developmental expression changes are similarly detectable in nuclear and cytoplasmic RNA, the compartmented transcriptomes become more distinct as the brain matures, perhaps reflecting increased utilization of nuclear retention as a regulatory strategy in adult brain. We examined potential mechanisms of this developmental divergence including alternative splicing, RNA editing, nuclear pore composition, RNA-binding protein motif enrichment, and RNA secondary structure. Intron retention is associated with greater nuclear abundance in a subset of transcripts, as is enrichment for several splicing factor binding motifs. Finally, we examined disease association with fraction-regulated gene sets and found nuclear-enriched genes were also preferentially enriched in gene sets associated with neurodevelopmental psychiatric disorders. These results suggest that although gene-level expression is globally comparable between fractions, nuclear retention of transcripts may play an underappreciated role in developmental regulation of gene expression in brain, particularly in genes whose dysregulation is related to neuropsychiatric disorders.
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http://dx.doi.org/10.1101/gr.250217.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961577PMC
January 2020

NURR1 and ERR1 Modulate the Expression of Genes of a Coexpression Network Enriched for Schizophrenia Risk.

J Neurosci 2020 01 6;40(4):932-941. Epub 2019 Dec 6.

Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy,

Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor () coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (, , ) or indexing coexpression in our module (, , , ) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment. In the present study, we provide and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.
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http://dx.doi.org/10.1523/JNEUROSCI.0786-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975285PMC
January 2020
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