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Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci [hFOB RNA-seq]

ABSTRACT: Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci [hFOB RNA-seq]

PROVIDER: PRJNA1246576 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32982525_1.fastq.gz	Fastqsanger.gz
	SRR32982525_2.fastq.gz	Fastqsanger.gz
	SRR32982526_1.fastq.gz	Fastqsanger.gz
	SRR32982526_2.fastq.gz	Fastqsanger.gz
	SRR32982527_1.fastq.gz	Fastqsanger.gz

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Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci

Project description:Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor SNPs demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (FDR correction<0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability (RCP)>0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis.

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Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci [hFOB RNA-seq]

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Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci

Project description:Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci

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Cell type-specific network analysis in Diversity Outbred mice identifies genes potentially responsible for human bone mineral density GWAS associations

Project description:Genome-wide association studies (GWASs) have identified many sources of genetic variation associated with bone mineral density (BMD), a clinical predictor of fracture risk and osteoporosis. Aside from the identification of causal genes, other difficult challenges to informing GWAS include characterizing the roles of predicted causal genes in disease and providing additional functional context, such as the cell type predictions or biological pathways in which causal genes operate. Leveraging single-cell transcriptomics (scRNA-seq) can assist in informing BMD GWAS by linking disease-associated variants to genes and providing a cell type context for which these causal genes drive disease. Here, we use large-scale scRNA-seq data from bone marrow–derived stromal cells cultured under osteogenic conditions (BMSC-OBs) from Diversity Outbred (DO) mice to generate cell type-specific networks and contextualize BMD GWAS-implicated genes. Using trajectories inferred from the scRNA-seq data, we identify networks enriched with genes that exhibit the most dynamic changes in expression across trajectories. We discover 21 network driver genes, which are likely to be causal for human BMD GWAS associations that colocalize with expression/splicing quantitative trait loci (eQTL/sQTL). These driver genes, including Fgfrl1 and Tpx2, along with their associated networks, are predicted to be novel regulators of BMD via their roles in the differentiation of mesenchymal lineage cells. In this work, we showcase the use of single-cell transcriptomics from mouse bone-relevant cells to inform human BMD GWAS and prioritize genetic targets with potential causal roles in the development of osteoporosis.

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Identification of target genes and regulatory networks for bone mineral density GWAS loci through systematic targeting and inhibition [hFOB BMD STING-seq]

Project description:Osteoporosis is characterized by low bone mineral density (BMD) and elevated fracture risk. Most BMD-associated GWAS variants lie in noncoding regions, complicating efforts to identify causal genes and mechanisms. To overcome this variant‑to‑function challenge, we previously developed STING‑seq, a framework integrating biobank‑scale GWAS with single‑cell CRISPR inhibition (CRISPRi) screening to directly connect noncoding cis‑regulatory elements (CREs) to their target genes. Applied to human fetal osteoblast (hFOB) cells across osteogenic differentiation, STING‑seq linked 76 CREs to 75 target genes at BMD loci. Arrayed CRISPRi and activation validated key CRE–gene relationships, including long‑range enhancers regulating CXCL12 (over 500 kb apart). We further uncovered trans‑regulatory networks and characterized the DAP3–YY1AP1 bidirectional promoter, demonstrating a role for DAP3 in mineralization via mitochondrial pathways. Together, these findings provide mechanistic insight into how noncoding GWAS variants shape osteoblast activity and highlight the genes and pathways that mediate genetic effects on BMD.

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Identification of Known and Novel Long Noncoding RNAs Potentially Responsible for the Effects of Bone Mineral Density (BMD) Genomewide Association Study (GWAS) Loci.

Project description:Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long noncoding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor single-nucleotide polymorphisms (SNPs) demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (false discovery rate [FDR] correction < 0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability [RCP] > 0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Cell type-specific network analysis in Diversity Outbred mice identifies genes potentially responsible for human bone mineral density GWAS associations

Project description:Cell type-specific network analysis in Diversity Outbred mice identifies genes potentially responsible for human bone mineral density GWAS associations

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Identification of target genes and regulatory networks for bone mineral density GWAS loci through systematic targeting and inhibition [hFOB ATAC-seq]

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Systems genetic analysis in Diversity Outbred mice informs human bone mineral density GWAS and identifies Qsox1 as a novel determinant of bone strength

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