Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.
Ontology highlight
ABSTRACT:
SUBMITTER: Kasela S
PROVIDER: S-EPMC8381345 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description: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.
| S-EPMC8057256 | biostudies-literature
Project description:PurposeIt is critical to identify putative causal targets for SARS coronavirus 2, which may guide drug repurposing options to reduce the public health burden of COVID-19.MethodsWe applied complementary methods and multiphased design to pinpoint the most likely causal genes for COVID-19 severity. First, we applied cross-methylome omnibus (CMO) test and leveraged data from the COVID-19 Host Genetics Initiative (HGI) comparing 9,986 hospitalized COVID-19 patients and 1,877,672 population controls. Second, we evaluated associations using the complementary S-PrediXcan method and leveraging blood and lung tissue gene expression prediction models. Third, we assessed associations of the identified genes with another COVID-19 phenotype, comparing very severe respiratory confirmed COVID versus population controls. Finally, we applied a fine-mapping method, fine-mapping of gene sets (FOGS), to prioritize putative causal genes.ResultsThrough analyses of the COVID-19 HGI using complementary CMO and S-PrediXcan methods along with fine-mapping, XCR1, CCR2, SACM1L, OAS3, NSF, WNT3, NAPSA, and IFNAR2 are identified as putative causal genes for COVID-19 severity.ConclusionWe identified eight genes at five genomic loci as putative causal genes for COVID-19 severity.
| S-EPMC8237048 | biostudies-literature
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.
| S-EPMC10081573 | biostudies-literature
Project description:We carried out a GWAS meta-analysis of combined mixed-ancestry schizophrenia, schizoaffective, and bipolar cohorts that resulted in the identification of six genome-wide significant loci, including one novel locus at chr8q24.3, encompassing TSNARE1 (P = 1.28 × 10(-9)). The analysis included a total of 13,394 cases and 34,676 controls. While the function of TSNARE1 remains unknown, bioinformatic predictions based on phylogenetic ancestry indicate it may have a vertebrate-specific function in intracellular protein transport and synaptic vesicle exocytosis.
| S-EPMC3810676 | biostudies-literature
Project description:Uveal melanoma, a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. A genome-wide association study of 259 uveal melanoma patients compared to 401 controls all of European ancestry revealed a candidate locus at chromosome 5p15.33 (region rs421284: OR = 1.7, CI 1.43-2.05). This locus was replicated in an independent set of 276 cases and 184 controls. In addition, risk variants from this region were positively associated with higher expression of CLPTM1L. In conclusion, the CLPTM1L region contains risk alleles for uveal melanoma susceptibility, suggesting that CLPTM1L could play a role in uveal melanoma oncogenesis.
| S-EPMC5542017 | biostudies-literature
Project description:A genome-wide association study (GWAS) involves examining representative SNPs obtained using high throughput technologies. A GWAS data set can entail a million SNPs and may soon entail many millions. In a GWAS researchers often investigate the correlation of each SNP with a disease. With so many hypotheses, it is not straightforward how to interpret the results. Strategies include using the Bonferroni correction to determine the significance of a model and Bayesian methods. However, when we are discovering new locus-disease associations, i.e., so called de novo discoveries, we should not just endeavor to determine the significance of particular models, but also concern ourselves with determining whether it is likely that we have any true discoveries, and if so how many of the highest ranking models we should investigate further. We develop a method based on a signal-to-noise ratio that targets this issue. We apply the method to a GWAS Alzheimer's data set.
| S-EPMC3243170 | biostudies-literature
Project description:Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.
| S-EPMC5943590 | biostudies-literature
Project description:Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.
| S-EPMC5868213 | biostudies-literature
Project description: Not available
| S-EPMC7612997 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10-5 in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P < 0.05), with the strongest enrichment observed in CD4+, CD8+, and regulatory T cells. We selected a putative causal variant, rs7962469, associated with ACVR1B expression in lung tissue for additional functional investigation, and reporter assays confirmed allele-specific regulatory activity for this variant in human bronchial epithelial and Jurkat immune cell lines. ACVR1B expression levels exhibit a nominally significant association with emphysema distribution. EABD-associated loci are preferentially enriched in regulatory elements of multiple cell types, most notably T-cell subsets. Multiple EABD loci colocalize to regulatory elements that are active across multiple tissues and cell types, and functional analyses confirm the presence of an EABD-associated functional variant that regulates ACVR1B expression, indicating that transforming growth factor-β signaling plays a role in the EABD phenotype. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
| S-EPMC6444627 | biostudies-literature