Dataset Information

Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.

ABSTRACT: To date the locus with the most robust human genetic association to COVID-19 susceptibility is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that mediate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of human biology.

SUBMITTER: Kasela S

PROVIDER: S-EPMC8057256 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.

Kasela Silva S Daniloski Zharko Z Jordan Tristan X TX tenOever Benjamin R BR Sanjana Neville E NE Lappalainen Tuuli T

medRxiv : the preprint server for health sciences 20210413

To date the locus with the most robust human genetic association to COVID-19 susceptibility is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that mediate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of h ...[more]

PMID: 33880488

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Project description:Genome-wide association studies demonstrated that the chromosome 3p31.21 locus was linked to the severity of COVID-19 disease. The SLC6A20 gene was reported to be one of the critical causal genes regulated by this locus. Various studies focused on demonstrating the severity of COVID-19 in cancer patients and reported that elevated SARS-CoV-2-associated gene expression might contribute to increased susceptibility for COVID-19 in cancer patients. Given that pan-cancer association for the COVID-19 causal gene SLC6A20 is lacking, we aimed to perform systematic profiling of SLC6A20 in different malignancies. Human Protein Atlas, UALCAN, and Hepatocellular Carcinoma (HCCDB) databases were used to assess SLC6A20 gene expression changes in The Cancer Genome Atlas samples with respect to their normal counterparts. GEPIA and TIMER2.0 databases were used to determine the correlation between SLC6A20 and COVID-19-associated genes. Different databases were used for identification of the correlation of SCL6A20 with infiltrating immune cells. The canSAR database was utilized to determine the association of SCL6A20 with immune profiling in different malignancies. The STRING database was utilized to determine the protein network interacting with SLC6A20. Here, we showed SLC6A20 mRNA expression in pan-cancer samples and their normal counterparts. Increased SCL6A20 expression was associated with tumor grade, and there was a positive correlation with SARS-CoV-2-associated genes. Furthermore, SLC6A20 expression was positively correlated with infiltrating neutrophils and immune-related signatures. Lastly, SLC6A20 expression was found to be associated with the angiotensin converting enzyme 2 homologue, TMEM27, suggesting a potential link between SLC6A20 and COVID-19. Taken together, these results suggest that elevated SLC6A20 levels might be partly responsible for increased susceptibility of cancer patients to COVID-19 disease. Therapeutic intervention strategies against SLC6A20 in cancer patients, alongside other treatment modalities, might offer a benefit in delaying COVID-19 disease.

Project description:Recent genome-wide association studies have identified 78 loci associated with Parkinson's disease susceptibility but the underlying mechanisms remain largely unclear. To identify likely causal variants for disease risk, we fine-mapped these Parkinson's-associated loci using four different fine-mapping methods. We then integrated multi-assay cell type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus single nucleotide polymorphism (SNPs) that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson's disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson's disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results. Large-scale studies comparing individuals with Parkinson's disease to age-matched controls have identified many regions of the genome associated with the disease. However, there is widespread correlation between different parts of the genome, making it difficult to tell which genetic variants cause Parkinson's and which are simply co-inherited with causal variants. We therefore applied a suite of statistical models to identify the most likely causal genetic variants (i.e. fine-mapping). We then linked these genetic variants with epigenomic and gene expression signatures across a wide variety of tissues and cell types to identify how these variants cause disease. Therefore, this study provides a comprehensive and robust list of cellular and molecular mechanisms that may serve as targets in the development of more effective Parkinson's therapeutics.

Dataset Information

Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.

Publications

Integrative approach identifies <i>SLC6A20</i> and <i>CXCR6</i> as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.

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