Dataset Information

Human brain single nucleus cell type enrichments in neurodegenerative diseases.

ABSTRACT:

Background

Single-cell RNA sequencing has opened a window into clarifying the complex underpinnings of disease, particularly in quantifying the relevance of tissue- and cell-type-specific gene expression.

Methods

To identify the cell types and genes important to therapeutic target development across the neurodegenerative disease spectrum, we leveraged genome-wide association studies, recent single-cell sequencing data, and bulk expression studies in a diverse series of brain region tissues.

Results

We were able to identify significant immune-related cell types in the brain across three major neurodegenerative diseases: Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Subsequently, putative roles of 30 fine-mapped loci implicating seven genes in multiple neurodegenerative diseases and their pathogenesis were identified.

Conclusions

We have helped refine the genetic regions and cell types effected across multiple neurodegenerative diseases, helping focus future translational research efforts.

SUBMITTER: Alvarado CX

PROVIDER: S-EPMC10680930 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Human brain single nucleus cell type enrichments in neurodegenerative diseases.

Alvarado Chelsea X CX Weller Cory A CA Johnson Nicholas N Leonard Hampton L HL Singleton Andrew B AB Reed Xylena X Blauewendraat Cornelis C Nalls Mike A MA

Research square 20231115

<h4>Background</h4>Single-cell RNA sequencing has opened a window into clarifying the complex underpinnings of disease, particularly in quantifying the relevance of tissue- and cell-type-specific gene expression.<h4>Methods</h4>To identify the cell types and genes important to therapeutic target development across the neurodegenerative disease spectrum, we leveraged genome-wide association studies, recent single-cell sequencing data, and bulk expression studies in a diverse series of brain regio ...[more]

PMID: 38014237

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Project description:BackgroundHepatocellular carcinoma (HCC) is a common primary liver cancer with poor overall survival. We hypothesized that there are HCC-associated cell-types that impact patient survival.MethodsWe combined liver single nucleus (snRNA-seq), single cell (scRNA-seq), and bulk RNA-sequencing (RNA-seq) data to search for cell-type differences in HCC. To first identify cell-types in HCC, adjacent non-tumor tissue, and normal liver, we integrated single-cell level data from a healthy liver cohort (n = 9 non-HCC samples) collected in the Strasbourg University Hospital; an HCC cohort (n = 1 non-HCC, n = 14 HCC-tumor, and n = 14 adjacent non-tumor samples) collected in the Singapore General Hospital and National University; and another HCC cohort (n = 3 HCC-tumor and n = 3 adjacent non-tumor samples) collected in the Dumont-UCLA Liver Cancer Center. We then leveraged these single cell level data to decompose the cell-types in liver bulk RNA-seq data from HCC patients' tumor (n = 361) and adjacent non-tumor tissue (n = 49) from the Cancer Genome Atlas (TCGA) multi-center cohort. For replication, we decomposed 221 HCC and 209 adjacent non-tumor liver microarray samples from the Liver Cancer Institute (LCI) cohort collected by the Liver Cancer Institute and Zhongshan Hospital of Fudan University.ResultsWe discovered a tumor-associated proliferative cell-type, Prol (80.4% tumor cells), enriched for cell cycle and mitosis genes. In the liver bulk tissue from the TCGA cohort, the proportion of the Prol cell-type is significantly increased in HCC and associates with a worse overall survival. Independently from our decomposition analysis, we reciprocally show that Prol nuclei/cells significantly over-express both tumor-elevated and survival-decreasing genes obtained from the bulk tissue. Our replication analysis in the LCI cohort confirmed that an increased estimated proportion of the Prol cell-type in HCC is a significant marker for a shorter overall survival. Finally, we show that somatic mutations in the tumor suppressor genes TP53 and RB1 are linked to an increase of the Prol cell-type in HCC.ConclusionsBy integrating liver single cell, single nucleus, and bulk expression data from multiple cohorts we identified a proliferating cell-type (Prol) enriched in HCC tumors, associated with a decreased overall survival, and linked to TP53 and RB1 somatic mutations.

Dataset Information

Human brain single nucleus cell type enrichments in neurodegenerative diseases.

Background

Methods

Results

Conclusions

Publications

Human brain single nucleus cell type enrichments in neurodegenerative diseases.

Similar Datasets

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