gsQTL: Associating genetic risk variants with gene sets by exploiting their shared variability DOI Creative Commons
Gerard A. Bouland, Niccolo Tesí, Ahmed Mahfouz

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

Abstract To investigate the functional significance of genetic risk loci identified through genome-wide association studies (GWASs), are linked to genes based on their capacity account for variation in gene expression, resulting expression quantitative trait (eQTL). Following this, set analyses commonly used gain insights into functionality. However, efficacy this approach is hampered by small effect sizes and burden multiple testing. We propose an alternative approach: instead examining cumulative associations individual within a set, we consider collective entire set. introduce concept QTL (gsQTL), show it be more adept at identifying links between variants specific sets. Notably, gsQTL experiences less susceptibility inflation or deflation significant enrichments compared with conventional methods. Furthermore, demonstrate broader applicability shared variability This evident scenarios such as coordinated regulation transcription factor differential expression.

Language: Английский

Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex DOI
Thomas Chartrand, Rachel Dalley, Jennie Close

et al.

Science, Journal Year: 2023, Volume and Issue: 382(6667)

Published: Oct. 12, 2023

Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion human neocortex marked by distinctive pyramidal neurons with extensive L1 branching, but whether interneurons are similarly diverse underexplored. Using Patch-seq recordings from neurosurgical tissue, we identified four transcriptomic subclasses mouse homologs, along distinct subtypes types unmatched in L1. Subclass subtype comparisons showed stronger differences were correlated strong morphoelectric variability dimensions variability. Accompanied greater thickness other cytoarchitecture changes, these findings suggest that has diverged evolution, reflecting the demands regulating expanded neocortical circuit.

Language: Английский

Citations

57
Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases DOI
Martin Kampmann

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(5), P. 351 - 371

Published: April 4, 2024

Language: Английский

Citations

36
Challenges and opportunities to computationally deconvolve heterogeneous tissue with varying cell sizes using single-cell RNA-sequencing datasets DOI Creative Commons
Sean K. Maden, Sang Ho Kwon, Louise A. Huuki-Myers

et al.

Genome biology, Journal Year: 2023, Volume and Issue: 24(1)

Published: Dec. 14, 2023

Abstract Deconvolution of cell mixtures in “bulk” transcriptomic samples from homogenate human tissue is important for understanding disease pathologies. However, several experimental and computational challenges impede transcriptomics-based deconvolution approaches using single-cell/nucleus RNA-seq reference atlases. Cells the brain blood have substantially different sizes, total mRNA, transcriptional activities, existing may quantify mRNA instead type proportions. Further, standards are lacking use atlases integrative analyses single-cell spatial transcriptomics data. We discuss how to approach these key with orthogonal “gold standard” datasets evaluating methods.

Language: Английский

Citations

25
CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis DOI Creative Commons

Avi J. Samelson,

Nabeela Ariqat, Justin McKetney

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 17, 2023

Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to aggregation subsequent dysfunction death, but underlying mechanisms unknown. To systematically uncover cellular factors controlling accumulation aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen iPSC-derived neurons. The uncovered expected pathways, including autophagy, also unexpected UFMylation GPI anchor synthesis. We discover that E3 ubiquitin ligase CUL5

Language: Английский

Citations

24
A suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types DOI Creative Commons
Yoav Ben‐Simon, Marcus Hooper, Sujatha Narayan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 10, 2024

The mammalian cortex is comprised of cells classified into types according to shared properties. Defining the contribution each cell type processes guided by essential for understanding its function in health and disease. We used transcriptomic epigenomic cortical taxonomies from mouse human define marker genes putative enhancers created a large toolkit transgenic lines enhancer AAVs selective targeting populations. report evaluation fifteen new driver lines, two reporter >800 different covering most subclasses cells. tools reported here as well scaled process tool creation modification enable diverse experimental strategies towards brain function.

Language: Английский

Citations

11
Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics DOI
Jessica E. Rexach, Yuyan Cheng, Lawrence Chen

et al.

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

10
The single-cell opioid responses in the context of HIV (SCORCH) consortium DOI Creative Commons
Seth A. Ament,

Rianne R. Campbell,

Mary Kay Lobo

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(12), P. 3950 - 3961

Published: June 15, 2024

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families communities. One seminal challenges in treating studying human populations is high prevalence co-morbid conditions, including an increased risk contracting a immunodeficiency virus (HIV) infection. Of ~15 million people who inject drugs globally, 17% persons HIV. Conversely, HIV factor for SUD because chronic pain syndromes, often encountered HIV, can lead opioid medications that turn increase addiction. We hypothesize exert shared effects on brain cell types, adaptations related neuroplasticity, neurodegeneration, neuroinflammation. Basic research needed refine our understanding these affected types adaptations. Studying context at single-cell level represents compelling strategy understand reciprocal interactions among both made feasible by availability large, extensively-phenotyped tissue collections have been amassed Neuro-HIV community. In addition, sophisticated animal models developed conditions provide means precisely evaluate specific exposures stages disease. propose genomics uniquely powerful technology characterize brain, integrating data from cohorts models. formed Single-Cell Opioid Responses Context (SCORCH) consortium carry out this strategy.

Language: Английский

Citations

6
BRAIN @ 10: A decade of innovation DOI Creative Commons
John Ngai

Neuron, Journal Year: 2024, Volume and Issue: 112(18), P. 3003 - 3006

Published: Sept. 1, 2024

Language: Английский

Citations

6
Generation of Mammalian Astrocyte Functional Heterogeneity DOI
Theresa Bartels, David H. Rowitch, Omer Ali Bayraktar

et al.

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(11), P. a041351 - a041351

Published: May 1, 2024

Mammalian astrocytes have regional roles within the brain parenchyma. Indeed, notion that are molecularly heterogeneous could help explain how central nervous system (CNS) retains embryonic positional information through development into specialized regions adulthood. A growing body of evidence supports concept morphological and molecular differences between in different regions, which might relate to their derivation from regionally patterned radial glia and/or local neuron inductive cues. Here, we review for encoded functions provide an integrated on lineage origins heterogeneity understand organization, as well emerging technologies identify further investigate novel astrocytes.

Language: Английский

Citations

4
In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease DOI Creative Commons
Lazaro M. Sanchez-Rodriguez, Ahmed Faraz Khan, Quadri Adewale

et al.

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: June 19, 2024

The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) tau deposits the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- tau-PET for 47 cognitively unimpaired 16 AD participants from Translational Biomarkers Aging Dementia cohort. Adverse activity impacts Aβ were quantified personalized dynamical models fitting pathology-mediated computational signals to participant’s real rs-fMRIs. Then, detected robust brain-wide associations between spatial profiles of Aβ-tau gene expression neurotypical transcriptome (Allen Human Brain Atlas). Within distinctive signature dysfunction, several genes have prominent roles microglial activation interactions tau. Moreover, vulnerability estimations revealed strong association patterns tau’s synergistic impact on ( q < 0.001). These results further support central role immune system neuroinflammatory pathogenesis. Neuronal pathologies also synaptic developmental processes. In addition, identified drug candidates vast LINCS library halt or reduce observed effects activity. Top-ranked pharmacological interventions target inflammatory, cancer cardiovascular pathways, including specific medications undergoing clinical evaluation AD. Our findings, based examination molecular-pathological-functional humans, may accelerate process bringing effective therapies into practice.

Language: Английский

Citations

4