Gabriel E. Hoffman
A5046862823- Genetic Associations and Epidemiology
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- Bioinformatics and Genomic Networks
- Genomics and Chromatin Dynamics
- Neuroinflammation and Neurodegeneration Mechanisms
- Gene expression and cancer classification
- RNA Research and Splicing
- Tryptophan and brain disorders
- Genetics and Neurodevelopmental Disorders
- Genomic variations and chromosomal abnormalities
- Genomics and Rare Diseases
- Autism Spectrum Disorder Research
- Long-Term Effects of COVID-19
- Genetic Mapping and Diversity in Plants and Animals
- Pluripotent Stem Cells Research
- Genetic and phenotypic traits in livestock
- CRISPR and Genetic Engineering
- Attention Deficit Hyperactivity Disorder
- Adipose Tissue and Metabolism
- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- Functional Brain Connectivity Studies
- Health, Environment, Cognitive Aging
- Bacterial Infections and Vaccines
Icahn School of Medicine at Mount Sinai
2016-2025
Allen Institute for Brain Science
2021-2025
James J. Peters VA Medical Center
2024
Translational Therapeutics (United States)
2024
Rush University Medical Center
2024
Christiana Care Health System
2023
Pediatrics and Genetics
2015-2022
Mount Sinai Medical Center
2022
Center for Information Technology
2020-2022
Genomics (United Kingdom)
2016-2020
Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments transcriptomic organization diseased brains are limited. In this work, we integrated genotypes RNA sequencing brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, bipolar disorder, as well controls. More than 25% the transcriptome exhibits differential splicing or expression,...
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 adult brain across 1866 individuals. The contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles many cell types; quantitative-trait loci (QTLs); further QTLs associated with chromatin, splicing, cell-type...
Abstract Background As large-scale studies of gene expression with multiple sources biological and technical variation become widely adopted, characterizing these drivers becomes essential to understanding disease biology regulatory genetics. Results We describe a statistical visualization framework, variancePartition, prioritize based on genome-wide summary, identify genes that deviate from the trend. Using linear mixed model, variancePartition quantifies in each trait attributable...
Abstract The availability of high-quality RNA-sequencing and genotyping data post-mortem brain collections from consortia such as CommonMind Consortium (CMC) the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) enable generation a large-scale cis- eQTL meta-analysis. Here we generate cerebral cortical 1433 samples available four cohorts (identifying >4.1 million significant >18,000 genes), well cerebellar 261 874,836 >10,000 genes). We find substantially improved...
Genes implicated in neuropsychiatric disorders are active human fetal brain, yet difficult to study a longitudinal fashion. We demonstrate that organoids from pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially genes and enhancers, with greatest changes occurring at transition stem progenitors. Networks of converging gene enhancer modules were assembled into six four global patterns...
Large-scale transcriptome studies with multiple samples per individual are widely used to study disease biology. Yet, current methods for differential expression inadequate cross-individual testing these repeated measures designs. Most problematic, we observe across datasets that can give reproducible false-positive findings driven by genetic regulation of gene expression, yet unrelated the trait interest. Here, introduce a statistical software package, dream, increases power, controls false...
Abstract 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 small effects lead to schizophrenia disorder. In order fill this gap between phenotype, we undertaken a multi-cohort genomics study postmortem brains from controls, individuals Here present public resource functional data...
To explore the developmental reorganization of three-dimensional genome brain in context neuropsychiatric disease, we monitored chromosomal conformations differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread remodeling contact map included interactions anchored common variant sequences that confer heritable risk for schizophrenia. We describe cell type-specific connectomes composed schizophrenia variants their distal targets, which...
Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into resource comprising >2.8 million nuclei from prefrontal cortex across 388 individuals. For 28 cell types, assessed population-level variation in expression and chromatin families drug targets. We identified >550,000 type-specific...
The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation the development more effective therapies. Here, we performed single-cell dissection schizophrenia-associated transcriptomic changes in human prefrontal cortex across 140 individuals two independent cohorts. Excitatory neurons were most affected cell group, with transcriptional converging on neurodevelopment synapse-related molecular pathways. Transcriptional alterations included known genetic risk...
Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays primary human cells from mid-gestation cortex cerebral organoids, we interrogated the cis-regulatory activity 102,767 open chromatin regions, including thousands sequences with cell type-specific accessibility variants associated brain regulation. In cells, identified 46,802 active enhancer 164 that alter activity. Activity was comparable...
The molecular organization of the human neocortex historically has been studied in context its histological layers. However, emerging spatial transcriptomic technologies have enabled unbiased identification transcriptionally defined domains that move beyond classic cytoarchitecture. We used Visium gene expression platform to generate a data-driven neuroanatomical atlas across anterior-posterior axis dorsolateral prefrontal cortex. Integration with paired single-nucleus RNA-sequencing data...
Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment regulatory elements in the developing brain. However, prioritizing risk genes mechanisms is challenging without a unified atlas. Across 672 diverse human brains, we identified 15,752 harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely...
Horse body size varies greatly due to intense selection within each breed. American Miniatures are less than one meter tall at the withers while Shires and Percherons can exceed two meters. The genetic basis for this variation is not known. We hypothesize that breed population structure of horse should simplify efforts identify genes controlling size. In support this, here we show with genome-wide association scans (GWAS) just four loci explain great majority variation. Unlike humans, which...
The power of human induced pluripotent stem cell (hiPSC)-based studies to resolve the smaller effects common variants within size cohorts that can be realistically assembled remains uncertain. We identified and accounted for a variety technical biological sources variation in large case/control schizophrenia (SZ) hiPSC-derived cohort neural progenitor cells neurons. Reducing stochastic differentiation process by correcting type composition boosted SZ signal increased concordance with...
African Pygmy groups show a distinctive pattern of phenotypic variation, including short stature, which is thought to reflect past adaptation tropical environment. Here, we analyze Illumina 1M SNP array data in three Western populations from Cameroon and neighboring Bantu-speaking agricultural with whom they have admixed. We infer genome-wide ancestry, scan for signals positive selection, perform targeted genetic association measured height variation. identify multiple regions throughout the...