RESUMEN
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.
Asunto(s)
COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2/genética , Estudio de Asociación del Genoma Completo , Haplotipos , Polimorfismo GenéticoRESUMEN
BACKGROUND: There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. METHODS: We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels. RESULTS: We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10-8) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10-10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10-8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10-4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10-5). CONCLUSIONS: We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).
Asunto(s)
Sistema del Grupo Sanguíneo ABO/genética , Betacoronavirus , Cromosomas Humanos Par 3/genética , Infecciones por Coronavirus/genética , Predisposición Genética a la Enfermedad , Neumonía Viral/genética , Polimorfismo de Nucleótido Simple , Insuficiencia Respiratoria/genética , Anciano , COVID-19 , Estudios de Casos y Controles , Cromosomas Humanos Par 9/genética , Infecciones por Coronavirus/complicaciones , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Italia , Masculino , Persona de Mediana Edad , Familia de Multigenes , Pandemias , Neumonía Viral/complicaciones , Insuficiencia Respiratoria/etiología , SARS-CoV-2 , EspañaRESUMEN
Background & Aims: Genetic and microbiome studies across patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have indicated that UC in PSC is a separate disease entity to primary UC, but expression studies for PSC are lacking. Methods: We conducted whole blood RNA sequencing experiments for 495 patients with UC, 220 patients with PSC (including 177 with UC), and 320 healthy controls from Germany and Norway. Differential expression analyses, gene ontology and coexpression analyses and random forest machine learning were performed to identify genes, ontologies and transcriptional features that discriminate diagnoses. Results: The blood transcriptome in UC and PSC is dominated by neutrophil activation genes (e.g. S100A12). In UC, but not in PSC (neither PSC alone nor patients with an additional diagnosis of UC [PSC/UC]), ribosomal, mitochondrial, and energy metabolism genes are upregulated in conjunction with antibody transcript expression (MZB1, IGJ). In PSC, there is an increase in modules related to apoptosis and expression of genes of interferon-I-related ontologies. Random forest analysis could poorly discriminate PSC alone from PSC/UC (AUROC 0.56), but could discriminate PSC, UC, and controls with high accuracy (AUROC UC vs. controls 0.95, PSC vs. controls 0.88, UC vs. PSC 0.986). The main coexpression modules relevant for distinguishing PSC, UC, and controls are enriched in neutrophil degranulation and antibody production genes. Conclusions: Supported by machine learning results, PSC and UC appear to be separate entities on a molecular level, while PSC/UC and PSC are indistinguishable. Impact and implications: Clinical and genetic studies suggest that the colitis-like symptoms in primary sclerosing cholangitis (PSC) represent a different disease entity from primary ulcerative colitis (UC). The present study supports this assumption with transcriptomic data from whole blood and describes notable differences in gene expression between primary UC and PSC, providing insights into the still unclear pathophysiology of both diseases. These findings are of interest to scientists seeking to decipher the molecular pathophysiology of both diseases and provide evidence that a redefinition of the PSC-UC phenotype should be considered. The study practically supports future molecular research by providing a large transcriptomic whole blood reference cohort.
RESUMEN
Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies for 23 tissues of the gut-brain-axis using genome-wide association studies data sets (total 180,592 patients) for Crohn's disease, ulcerative colitis, primary sclerosing cholangitis, schizophrenia, bipolar disorder, major depressive disorder and attention-deficit/hyperactivity disorder. We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory ulcerative colitis) as shared susceptibility genes with transcriptome-wide significance both for Crohn's disease, ulcerative colitis and schizophrenia, largely explaining fine-mapped association signals at nearby genome-wide association study susceptibility loci. Analysis of bulk and single-cell RNA-sequencing data showed that PPP3CA expression was strongest in neurons and in enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the gut-brain-axis. PPP3CA together with three further suggestive loci can be linked to calcineurin-related signaling pathways such as NFAT activation or Wnt.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades Inflamatorias del Intestino/genética , Esquizofrenia/genética , Transcriptoma , Eje Cerebro-Intestino/fisiología , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Sistema de Registros , Esquizofrenia/metabolismo , Distribución TisularRESUMEN
Despite the increasing knowledge about factors shaping the human microbiome, the host genetic factors that modulate the skin-microbiome interactions are still largely understudied. This contrasts with recent efforts to characterize host genes that influence the gut microbiota. Here, we investigated the effect of genetics on skin microbiota across three different skin microenvironments through meta-analyses of genome-wide association studies (GWAS) of two population-based German cohorts. We identified 23 genome-wide significant loci harboring 30 candidate genes involved in innate immune signaling, environmental sensing, cell differentiation, proliferation and fibroblast activity. However, no locus passed the strict threshold for study-wide significance (P < 6.3 × 10-10 for 80 features included in the analysis). Mendelian randomization (MR) analysis indicated the influence of staphylococci on eczema/dermatitis and suggested modulating effects of the microbiota on other skin diseases. Finally, transcriptional profiles of keratinocytes significantly changed after in vitro co-culturing with Staphylococcus epidermidis, chosen as a representative of skin commensals. Seven candidate genes from the GWAS were found overlapping with differential expression in the co-culturing experiments, warranting further research of the skin commensal and host genetic makeup interaction.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Humanos , Estudio de Asociación del Genoma Completo , Microbiota/genética , Piel , Inmunidad Innata/genética , Microbioma Gastrointestinal/genéticaRESUMEN
RNA-Sequencing (RNA-Seq) of peripheral blood can be a valuable source of information for investigating the status and mechanism of diseases. However, blood contains 50-80% unwanted hemoglobin (Hb) transcripts. Lexogen's QuantSeq mRNA-Seq-Kit for Illumina RNA-Seq features a 'Globin Block' (GB) module that depletes Hb cDNAs during library preparation. Here, we aimed to assess GB's effectiveness and checked for technical biases attributable to GB. Using whole blood total RNA samples of 91 healthy individuals, we sequenced 91 pairs of GB and non-blocked samples (noGB) on Illumina HiSeq2500 and 8 pairs of GB/noGB technical replicates on HiSeq4000. GB reduced the fraction of Hb transcripts from 43% (s.d. 14%) to 8.0% (s.d. 4.3%). From GB samples we detected 1,397 more expressed genes at approximately 11 million reads per RNA-isolate. Enrichment and differential expression analyses did not reveal significant differences for GB and noGB samples with respect to molecular function. In contrast to results from studies that have examined the performance of GB during RNA isolation, we were able to assign GB to corresponding noGB samples (from multiple sequencing runs on HiSeq2500) with at least 89.8% accuracy from the complete correlation matrix of all GB/GB, noGB/noGB and GB/noGB pairs. However, the use of different sequencers (HiSeq2500 vs HiSeq4000) impaired assignment of technical replicates, whereas assignment of GB to corresponding noGB samples worked perfectly when sequencing on one lane on HiSeq4000. Lexogen's GB RNA-Seq module is a valuable addition during mRNA-Seq library preparation which works even with low amounts of input total RNA (50 ng per sample). GB facilitated the detection of low abundant transcripts and yielded more non-hemoglobin reads, while preserving biological information. We observed that differences in sequencing run and platform have a far greater effect on technical variation than the use of GB.