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Article ; Online: Convergence of the dysregulated regulome in schizophrenia with polygenic risk and evolutionarily constrained enhancers.

Dong, Pengfei / Voloudakis, Georgios / Fullard, John F / Hoffman, Gabriel E / Roussos, Panos

2023

Abstract: Enhancers play an essential role in the etiology of schizophrenia; however, the dysregulation of enhancer activity and its impact on the regulome in schizophrenia remains understudied. To address this gap in our knowledge, we assessed enhancer and gene ... ...

Abstract	Enhancers play an essential role in the etiology of schizophrenia; however, the dysregulation of enhancer activity and its impact on the regulome in schizophrenia remains understudied. To address this gap in our knowledge, we assessed enhancer and gene expression in 1,382 brain samples comprising cases with schizophrenia and unaffected controls. Dysregulation of enhancer expression was concordant with changes in gene expression, and was more closely associated with schizophrenia polygenic risk, suggesting that enhancer dysregulation is proximal to the genetic etiology of the disease. Modeling the shared variance of cis-coordinated genes and enhancers revealed a gene regulatory program that was highly associated with genetic vulnerability to schizophrenia. By integrating coordinated factors with evolutionary constraints, we found that enhancers acquired during human evolution are more likely to regulate genes that are implicated in neuropsychiatric disorders and, thus, hold potential as therapeutic targets. Our analysis provides a systematic view of regulome dysregulation in schizophrenia and highlights its convergence with schizophrenia polygenic risk and human-gained enhancers.
Language	English
Publishing date	2023-12-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-023-02370-y
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Article: Alzheimer's disease transcriptional landscape in ex-vivo human microglia.

Roussos, Panos / Kosoy, Roman / Fullard, John / Bendl, Jaroslav / Kleopoulos, Steven / Shao, Zhiping / Argyriou, Stathis / Mathur, Deepika / Vicari, James / Ma, Yixuan / Humphrey, Jack / Brophy, Erica / Raj, Towfique / Katsel, Pavel / Voloudakis, Georgios / Lee, Donghoon / Bennett, David / Haroutunian, Vahram / Hoffman, Gabriel

Research square

2024

Abstract: Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's Disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly ... ...

Abstract	Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's Disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present the transcriptional landscape of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, including 63 patients representing the full spectrum of clinical and pathological severity of AD. We identified transcriptional changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions. Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes. We identified changes in gene-gene coordination in AD, dysregulation of co-expression modules, and disease subtypes with distinct gene expression. Taken together, these data further our understanding of the key role of microglia in AD biology and nominate candidates for therapeutic intervention.
Language	English
Publishing date	2024-01-26
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3851590/v1
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Article: Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet.

Hoffman, Gabriel E / Lee, Donghoon / Bendl, Jaroslav / Fnu, Prashant / Hong, Aram / Casey, Clara / Alvia, Marcela / Shao, Zhiping / Argyriou, Stathis / Therrien, Karen / Venkatesh, Sanan / Voloudakis, Georgios / Haroutunian, Vahram / Fullard, John F / Roussos, Panos

Research square

2023

Abstract: Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds of subjects and millions of cells. These studies promise to give unprecedented insight into the cell type specific biology of ... ...

Abstract	Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds of subjects and millions of cells. These studies promise to give unprecedented insight into the cell type specific biology of human disease. Yet performing differential expression analyses across subjects remains difficult due to challenges in statistical modeling of these complex studies and scaling analyses to large datasets. Our open-source R package dreamlet (DiseaseNeurogenomics.github.io/dreamlet) uses a pseudobulk approach based on precision-weighted linear mixed models to identify genes differentially expressed with traits across subjects for each cell cluster. Designed for data from large cohorts, dreamlet is substantially faster and uses less memory than existing workflows, while supporting complex statistical models and controlling the false positive rate. We demonstrate computational and statistical performance on published datasets, and a novel dataset of 1.4M single nuclei from postmortem brains of 150 Alzheimer's disease cases and 149 controls.
Language	English
Publishing date	2023-05-02
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2705625/v1
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Article: Detecting and Adjusting for Hidden Biases due to Phenotype Misclassification in Genome-Wide Association Studies.

Burstein, David / Hoffman, Gabriel / Mathur, Deepika / Venkatesh, Sanan / Therrien, Karen / Fanous, Ayman H / Bigdeli, Tim B / Harvey, Philip D / Roussos, Panos / Voloudakis, Georgios

medRxiv : the preprint server for health sciences

2023

Abstract: With the advent of healthcare-based genotyped biobanks, genome-wide association studies (GWAS) leverage larger sample sizes, incorporate patients with diverse ancestries and introduce noisier phenotypic definitions. Yet the extent and impact of ... ...

Abstract	With the advent of healthcare-based genotyped biobanks, genome-wide association studies (GWAS) leverage larger sample sizes, incorporate patients with diverse ancestries and introduce noisier phenotypic definitions. Yet the extent and impact of phenotypic misclassification on large-scale datasets is not currently well understood due to a lack of statistical methods to estimate relevant parameters from empirical data. Here, we develop a statistical method and scalable software, PheMED, Phenotypic Measurement of Effective Dilution, to quantify phenotypic misclassification across GWAS using only summary statistics. We illustrate how the parameters estimated by PheMED relate to the negative and positive predictive value of the labeled phenotype, compared to ground truth, and how misclassification of the phenotype yields diluted effect-sizes of variant-phenotype associations. Furthermore, we apply our methodology to detect multiple instances of statistically significant dilution in real-world data. We demonstrate how effective dilution biases downstream GWAS replication and heritability analyses despite utilizing current best practices, and provide a dilution-aware meta-analysis approach that outperforms existing methods. Consequently, we anticipate that PheMED will be a valuable tool for researchers to address phenotypic data quality issues both within and across cohorts.
Language	English
Publishing date	2023-01-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.17.23284670
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Article: Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet.

bioRxiv : the preprint server for biology

2023

Abstract	Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds of subjects and millions of cells. These studies promise to give unprecedented insight into the cell type specific biology of human disease. Yet performing differential expression analyses across subjects remains difficult due to challenges in statistical modeling of these complex studies and scaling analyses to large datasets. Our open-source R package dreamlet (DiseaseNeurogenomics.github.io/dreamlet) uses a pseudobulk approach based on precision-weighted linear mixed models to identify genes differentially expressed with traits across subjects for each cell cluster. Designed for data from large cohorts, dreamlet is substantially faster and uses less memory than existing workflows, while supporting complex statistical models and controlling the false positive rate. We demonstrate computational and statistical performance on published datasets, and a novel dataset of 1.4M single nuclei from postmortem brains of 150 Alzheimer's disease cases and 149 controls.
Language	English
Publishing date	2023-03-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.17.533005
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Article ; Online: Genome-wide analysis of a model-derived binge eating disorder phenotype identifies risk loci and implicates iron metabolism.

Burstein, David / Griffen, Trevor C / Therrien, Karen / Bendl, Jaroslav / Venkatesh, Sanan / Dong, Pengfei / Modabbernia, Amirhossein / Zeng, Biao / Mathur, Deepika / Hoffman, Gabriel / Sysko, Robyn / Hildebrandt, Tom / Voloudakis, Georgios / Roussos, Panos

Nature genetics

2023 Volume 55, Issue 9, Page(s) 1462–1470

Abstract: Binge eating disorder (BED) is the most common eating disorder, yet its genetic architecture remains largely unknown. Studying BED is challenging because it is often comorbid with obesity, a common and highly polygenic trait, and it is underdiagnosed in ... ...

Abstract	Binge eating disorder (BED) is the most common eating disorder, yet its genetic architecture remains largely unknown. Studying BED is challenging because it is often comorbid with obesity, a common and highly polygenic trait, and it is underdiagnosed in biobank data sets. To address this limitation, we apply a supervised machine-learning approach (using 822 cases of individuals diagnosed with BED) to estimate the probability of each individual having BED based on electronic medical records from the Million Veteran Program. We perform a genome-wide association study of individuals of African (n = 77,574) and European (n = 285,138) ancestry while controlling for body mass index to identify three independent loci near the HFE, MCHR2 and LRP11 genes and suggest APOE as a risk gene for BED. We identify shared heritability between BED and several neuropsychiatric traits, and implicate iron metabolism in the pathophysiology of BED. Overall, our findings provide insights into the genetics underlying BED and suggest directions for future translational research.
MeSH term(s)	Humans ; Binge-Eating Disorder/genetics ; Binge-Eating Disorder/psychology ; Genome-Wide Association Study ; Obesity/genetics ; Phenotype ; Iron
Chemical Substances	Iron (E1UOL152H7)
Language	English
Publishing date	2023-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01464-1
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 46: Show issues

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Article ; Online: Assessment of somatic single-nucleotide variation in brain tissue of cases with schizophrenia.

Fullard, John F / Charney, Alexander W / Voloudakis, Georgios / Uzilov, Andrew V / Haroutunian, Vahram / Roussos, Panos

Translational psychiatry

2019 Volume 9, Issue 1, Page(s) 21

Abstract: The genetic architecture of schizophrenia (SCZ) includes numerous risk loci across a range of frequencies and sizes, including common and rare single-nucleotide variants and insertions/deletions (indels), as well as rare copy number variants (CNVs). ... ...

Abstract	The genetic architecture of schizophrenia (SCZ) includes numerous risk loci across a range of frequencies and sizes, including common and rare single-nucleotide variants and insertions/deletions (indels), as well as rare copy number variants (CNVs). Despite the clear heritability of the disease, monozygotic twins are discordant for SCZ at a significant rate. Somatic variants-genetic changes that arise after fertilization rather than through germline inheritance-are widespread in the human brain and known to contribute to risk for both rare and common neuropsychiatric conditions. The contribution of somatic variants in the brain to risk of SCZ remains to be determined. In this study, we surveyed somatic single-nucleotide variants (sSNVs) in the brains of controls and individuals with SCZ (n = 10 and n = 9, respectively). From each individual, whole-exome sequencing (WES) was performed on DNA from neuronal and non-neuronal nuclei isolated by fluorescence activated nuclear sorting (FANS) from frozen postmortem prefrontal cortex (PFC) samples, as well as DNA extracted from temporal muscle as a reference. We identified an increased burden of sSNVs in cases compared to controls (SCZ rate = 2.78, control rate = 0.70; P = 0.0092, linear mixed effects model), that included a higher rate of non-synonymous and loss-of-function variants (SCZ rate = 1.33, control rate = 0.50; P = 0.047, linear mixed effects model). Our findings suggest sSNVs in the brain may constitute an additional component of the complex genetic architecture of SCZ. This perspective argues for the need to further investigate somatic variation in the brain as an explanation of the discordance in monozygotic twins and a potential guide to the identification of novel therapeutic targets.
MeSH term(s)	Brain/pathology ; Case-Control Studies ; DNA Copy Number Variations ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide ; Schizophrenia/genetics ; Schizophrenia/pathology ; Twins, Monozygotic/genetics ; Whole Exome Sequencing
Language	English
Publishing date	2019-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-018-0342-0
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Article: The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development.

Research square

2023

Abstract: Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of ... ...

Abstract	Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and controls. A per-sample disease pseudotime was positively associated with genetic liability for schizophrenia. Organizing chromatin into
Language	English
Publishing date	2023-10-02
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3393581/v1
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Article: The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development.

medRxiv : the preprint server for health sciences

2023

Abstract	Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and controls. A per-sample disease pseudotime was positively associated with genetic liability for schizophrenia. Organizing chromatin into
Language	English
Publishing date	2023-10-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.02.23296067
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Article ; Online: The product of the γ-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis.

Warren, Noel A / Voloudakis, Georgios / Yoon, Yonejung / Robakis, Nikolaos K / Georgakopoulos, Anastasios

Cellular and molecular life sciences : CMLS

2018 Volume 75, Issue 15, Page(s) 2813–2826

Abstract: Presenilin-1 (PS1) gene encodes the catalytic component of γ-secretase, which proteolytically processes several type I transmembrane proteins. We here present evidence that the cytosolic peptide efnB2/CTF2 produced by the PS1/γ-secretase cleavage of ... ...

Abstract	Presenilin-1 (PS1) gene encodes the catalytic component of γ-secretase, which proteolytically processes several type I transmembrane proteins. We here present evidence that the cytosolic peptide efnB2/CTF2 produced by the PS1/γ-secretase cleavage of efnB2 ligand promotes EphB4 receptor-dependent angiogenesis in vitro. EfnB2/CTF2 increases endothelial cell sprouting and tube formation, stimulates the formation of angiogenic complexes that include VE-cadherin, Raf-1 and Rok-α, and increases MLC2 phosphorylation. These functions are mediated by the PDZ-binding domain of efnB2. Acute downregulation of PS1 or inhibition of γ-secretase inhibits the angiogenic functions of EphB4 while absence of PS1 decreases the VE-cadherin angiogenic complexes of mouse brain. Our data reveal a mechanism by which PS1/γ-secretase regulates efnB2/EphB4 mediated angiogenesis.
MeSH term(s)	Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Animals ; Antigens, CD/metabolism ; Cadherins/metabolism ; Cattle ; Cells, Cultured ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelial Cells/physiology ; Enzyme Inhibitors/pharmacology ; Ephrin-B2/metabolism ; Mice, Knockout ; Microscopy, Confocal ; Neovascularization, Physiologic/drug effects ; Peptides/metabolism ; Peptides/pharmacology ; RNA Interference ; Receptor, EphB4/metabolism
Chemical Substances	Antigens, CD ; Cadherins ; Enzyme Inhibitors ; Ephrin-B2 ; Peptides ; cadherin 5 ; Receptor, EphB4 (EC 2.7.10.1) ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2018-02-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-018-2762-7
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