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Massively parallel reporter assays investigate shared genetic variants of eight psychiatric disorders

ABSTRACT: Massively parallel reporter assays investigate shared genetic variants of eight psychiatric disorders

PROVIDER: PRJNA1020890 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26171900.fastq.gz	Fastqsanger.gz
	SRR26171901.fastq.gz	Fastqsanger.gz
	SRR26171902.fastq.gz	Fastqsanger.gz
	SRR26171903.fastq.gz	Fastqsanger.gz
	SRR26171904.fastq.gz	Fastqsanger.gz

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Massively parallel reporter assays investigate shared genetic variants of eight psychiatric disorders

Project description:A meta-genome-wide association study encompassing eight psychiatric disorders has shed light on the genetic architecture of pleiotropy. However, mechanisms underlying pleiotropic effects of these variants remain to be investigated. We conducted a massively parallel reporter assay to decipher the regulatory logic of variants with disease-specific and pleiotropic effects. Pleiotropic variants differ from disease-specific variants by manifesting chromatin accessibility that extends across diverse cell types in the neuronal lineage, and altering motifs for transcription factors with higher connectivity in protein-protein interaction (PPI) networks. Next, we mapped pleiotropic and disease-specific variants to putative target genes, which may offer insights into potential mechanisms of pleiotropy. Compared with disease-specific genes, pleiotropic genes demonstrate associations with generic biological pathways, widespread temporal dynamics during neuronal lineage, and higher connectivity in PPI networks. Collectively, variants exert pleiotropic effects by regulating genes involved in global biological functions.

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Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Project description:A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches. In vitro CRISPR perturbation of selected variants confirmed the variant-gene relationships, and in vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.

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Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Project description:A meta-genome-wide association study across eight psychiatric disorders has shed light on the genetic architecture of pleiotropy in major psychiatric disorders. However, the mechanisms underlying pleiotropic effects of the associated variants remain to be investigated. We conducted a massively parallel reporter assay to decipher the regulatory logic of variants with disorder-specific and pleiotropic effects. We found that pleiotropic variants differ from disorder-specific variants by manifesting chromatin accessibility that extends across diverse cell types in the neuronal lineage, as well as by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. Next, we mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches. CRISPR-mediated validation confirmed the functional impact of selected variants on predicted target genes. Furthermore, in vivo CRISPR perturbation of a pleiotropic and a disease-specific gene suggests that pleiotropy is mediated by the regulation of genes expressed in a broader range of neuronal types and with higher network connectivity.

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Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

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