The worldwide covid-19 genetic risk scenario

Populations respond differently to the current global pandemic of covid-19. This study explores the role of individual factors in the differential response to covid-19, by looking at the genetic background of worldwide populations. Significant SNPs (susceptibility: rs286914/rs12329760; severity: rs657152/rs11385942) were selected from the literature and their allelic frequencies used to calculate the probability of having multiple risk alleles in each population. Portuguese (n=623), Spanish (n=9761) and Italian (n=6363) populations data are observed values, whereas data for world populations are estimations based on public information. All populations, even those with European ancestry (Portuguese/Spanish/Italian), were significantly different from the European population in both covid-19 susceptibility and severity (all p-values < 0.0001)(Fig. 1). Our study highlights a genetic heterogeneity across world populations, especially within European subpopulations. There is a need to build a European genetic map so that differences in the distribution of relevant alleles can be easily accessed and used to better manage the populations, ultimately, safeguarding those under higher genetic risk.publishe

Genetic risk for covid-19 outcomes in COPD

There is strong individual variability in both susceptibility and clinical response to covid-19 infection. People with chronic obstructive pulmonary disease (COPD) constitute one of covid-19 risk groups for poor outcomes upon infection. This study contributes to unveil the underlying reasons for such outcomes by looking at the genetic background of people with COPD. 255 people with COPD (66±9y; 72%♂; FEV1 53.01±20.31pp) and 243 controls (67±10y; 80%♂; FEV1 100.46±19.19pp) were clinically characterized and genotyped using saliva samples. Covid-19 associated SNPs from the literature (susceptibility: rs286914/rs12329760; severity: rs657152/rs11385942) were assessed and their allelic frequencies used to calculate the probability of having multiple risk alleles in both groups. Polygenic risk analysis was also conducted. No differences in genetic risk for covid-19 susceptibility or severity were found between groups (all p-values > 0.01), either considering individual risk alleles, allelic combinations or polygenic risk scores (Fig. 1). These results suggest a low genetic contribution for the poor covid-19 outcomes observed in people with COPD.publishe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Sequenciação de DNA – NGS manual de boas práticas

Sem resumo disponível.publishe

Multiomics approaches to study ageing and age-related diseases in research model organisms and in humans

Sem resumo disponível.Not Publishe

Integration of segmented regression analysis with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues

Gene expression alterations occurring with aging have been described for a multitude of species, organs, and cell types. However, most of the underlying studies rely on static comparisons of mean gene expression levels between age groups and do not account for the dynamics of gene expression throughout the lifespan. These studies also tend to disregard the pairwise relationships between gene expression profiles, which may underlie commonly altered pathways and regulatory mechanisms with age. To overcome these limitations, we have combined segmented regression analysis with weighted gene correlation network analysis (WGCNA) to identify high-confidence signatures of aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice in a publicly available RNA-Seq dataset (GSE132040). Functional enrichment analysis of the overlap of genes identified in both approaches showed that immune- and inflammation-related responses are prominently altered in the brain and the liver, while in the heart and the muscle, aging affects amino and fatty acid metabolism, and tissue regeneration, respectively, which reflects an age-related global loss of tissue function. We also explored sexual dimorphism in the aging mouse transcriptome and found the liver and the muscle to have the most pronounced gender differences in gene expression throughout the lifespan, particularly in proteostasis-related pathways. While the data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, which we highlight as important features of murine tissue physiological aging.publishe

The genomics facility of iBiMED: bioinformatics lab

The Genomics facility of iBiMED (iBiGEN), provides genomics services, including bioinformatics and statistical analysis to iBiMED researchers, and to external users. Since our start, in 2018, the bioinformatic lab have carried out 52 studies at a genomic scale, including de novo genome sequencing with variant detection (SNPs, indels, CNVs, LOH), whole exome or gene panel sequencing, RNA sequencing analysis (total RNA, mRNA, small RNA, LncRNA), as well as DNA microarrays for cohort genotyping in populational studies and gene expression assessment. During the COVID-19 pandemics, iBiGEN joined the national effort to monitor SARS-COV2 genomic variants and have analyzed 1121 samples through genome sequencing and variant detection. As part of iBiGEN, the Bioinformatics laboratory is equipped with 16 desktops (for resident and temporary users), one server and one cluster for storage and high-level processing. It gathers a team composed of one senior bioinformatician, one bioinformatic technician, two PostDocs and five PhD students. The data-analysis workflows implemented use open-source programs automatized with housemade scripts of several coding languages (bash, Python and R). The workflows are based on state-of-the-art methods and support different data types, formats, origins, and reference organisms.Not Publishe

Cell Fate Analysis of Embryonic Ventral Mesencephalic Grafts in the 6-OHDA Model of Parkinson's Disease

<div><p>Evidence from carefully conducted open label clinical trials suggested that therapeutic benefit can be achieved by grafting fetal dopaminergic (DAergic) neurons derived from ventral mesencephalon (VM) into the denervated striatum of Parkinson's disease (PD) patients. However, two double-blind trials generated negative results reporting deleterious side effects such as prominent dyskinesias. Heterogeneous composition of VM grafts is likely to account for suboptimal clinical efficacy.</p> <p>We consider that gene expression patterns of the VM tissue needs to be better understood by comparing the genetic signature of the surviving and functioning grafts with the cell suspensions used for transplantation. In addition, it is crucial to assess whether the grafted cells exhibit the DAergic phenotype of adult substantia nigra pars compacta (SNpc). To investigate this further, we used a GFP reporter mouse as source of VM tissue that enabled the detection and dissection of the grafts 6 weeks post implantation. A comparative gene expression analysis of the VM cell suspension and grafts revealed that VM grafts continue to differentiate post-implantation. In addition, implanted grafts showed a mature SNpc-like molecular DAergic phenotype with similar expression levels of TH, Vmat2 and Dat. However, by comparing gene expression of the adult SNpc with dissected grafts we detected a higher expression of progenitor markers in the grafts. Finally, when compared to the VM cell suspension, post-grafting there was a higher expression of markers inherent to glia and other neuronal populations.</p> <p>In summary, our data highlight the dynamic development of distinctive DAergic and non-DAergic gene expression markers associated with the maturation of VM grafts in vivo. The molecular signature of VM grafts and its functional relevance should be further explored in future studies aimed at the optimization of DAergic cell therapy approaches in PD.</p> </div

Evaluation of the genetic risk for COVID-19 outcomes in COPD and differences among worldwide populations

Populations seem to respond differently to the global pandemic of severe acute respiratory syndrome coronavirus 2. Recent studies show individual variability in both susceptibility and clinical response to COVID-19 infection. People with chronic obstructive pulmonary disease (COPD) constitute one of COVID-19 risk groups, being already associated with a poor prognosis upon infection. This study aims contributing to unveil the underlying reasons for such prognosis in people with COPD and the variability in the response observed across worldwide populations, by looking at the genetic background as a possible answer to COVID-19 infection response heterogeneity. SNPs already associated with susceptibility to COVID-19 infection (rs286914 and rs12329760) and severe COVID-19 with respiratory failure (rs657152 and rs11385942) were assessed and their allelic frequencies used to calculate the probability of having multiple risk alleles. This was performed on a Portuguese case-control COPD cohort, previously clinically characterized and genotyped from saliva samples, and also on worldwide populations (European, Spanish, Italian, African, American and Asian), using publicly available frequencies data. A polygenic risk analysis was also conducted on the Portuguese COPD cohort for the two mentioned phenotypes, and also for hospitalization and survival to COVID-19 infection. No differences in genetic risk for COVID-19 susceptibility, hospitalization, severity or survival were found between people with COPD and the control group (all p-values > 0.01), either considering risk alleles individually, allelic combinations or polygenic risk scores. All populations, even those with European ancestry (Portuguese, Spanish and Italian), showed significant differences from the European population in genetic risk for both COVID-19 susceptibility and severity (all p-values < 0.0001). Our results indicate a low genetic contribution for COVID-19 infection predisposition or worse outcomes observed in people with COPD. Also, our study unveiled a high genetic heterogeneity across major world populations for the same alleles, even within European sub-populations, demonstrating the need to build a higher resolution European genetic map, so that differences in the distribution of relevant alleles can be easily accessed and used to better manage diseases, ultimately, safeguarding populations with higher genetic predisposition to such diseases.publishe