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A SARS-CoV2 super-spreading event occurred during carnival in a small town in Germany. Due to the rapidly imposed lockdown and its relatively closed community, this town was seen as an ideal model to investigate the infection fatality rate (IFR). Here, a 7-day seroepidemiological observational study was performed to collect information and biomaterials from a random, household-based study population. The number of infections was determined by IgG analyses and PCR testing. We found that of the 919 individuals with evaluable infection status, 15.5% (95% CI:[12.3%; 19.0%]) were infected. This is a fivefold higher rate than the reported cases for this community (3.1%). 22.2% of all infected individuals were asymptomatic. The estimated IFR was 0.36% (95% CI:[0.29%; 0.45%]) for the community and 0.35% [0.28%; 0.45%] when age-standardized to the population of the community. Participation in carnival increased both infection rate (21.3% versus 9.5%, p  < 0.001) and number of symptoms (estimated relative mean increase 1.6, p  = 0.007). While the infection rate here is not representative for Germany, the IFR is useful to estimate the consequences of the pandemic in places with similar healthcare systems and population characteristics. Whether the super-spreading event not only increases the infection rate but also affects the IFR requires further investigation. Here the authors present a SARS-CoV2 seroepidemiological observational study from a random, household-based study population in a small town in Germany, showing the effect of a super-spreading event on infection rate, severity, and potentially infection fatality rate.

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8 + T-cells and CD4 + T-cells including T H 0, T H 1 and T H 17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset ( p= 2 × 10 −89 ). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis. Psoriasis is an immune-mediated skin disease with a complex genetic architecture. Here, Elder and colleagues identify 16 novel psoriasis susceptibility loci using GWAS meta-analysis with a combined effective sample size of over 39,000 individuals.

Objectives: C-Reactive Protein (CRP) values are partly determined by variation at the CRP gene locus, but also influenced by socioeconomic position (SEP) and related lifestyle factors. As gene-by-SEP interactions have been suggested for traits associated with CRP and SEP (e.g., BMI, coronary artery disease), the aim of this study was to investigate the strength of a possible interaction between a CRP gene common variant (rs4287174) and SEP in their joint influence on CRP levels in a population-based study sample. Methods: Single nucleotide polymorphism rs4287174 was genotyped in 4065 participants (aged 45–75 years) of the Heinz Nixdorf Recall study, a population-based prospective cohort. SEP indicators (education and income), risk factors (i.e., body mass index (BMI), total cholesterol, diabetes mellitus, coronary artery calcification, current smoking, hypertension, diet, no exercise) and blood serum CRP (mg/dl) were assessed at study baseline. Interaction analysis was based on linear regression and on stratified analyses (genetic effect stratified by SEP and vice versa) adjusted for age and sex using log e (CRP + 1) as dependent variable. Results: Low SEP and rs4287174 T allele were both associated with higher CRP values. The strongest genetic effect was observed in the lowest educational group (≤ 10 years of education) with an exp(β) indicating 1.058-fold (95%-CI: 1.018; 1.100) average CRP values per additional T allele, while in the highest educational group (≥ 18 years) the association was considerably less strong (exp(β): 1.005 (95%-CI: 0.975; 1.037)). After including rs4287174-by-education interaction terms in the regression analysis, interaction was indicated suggesting stronger genetic effects on CRP in low SEP groups (exp(β interaction ): 1.056 (95%-CI: 1.005; 1.108); p  = 0.029). The observed interaction did not seem to be substantially mediated by the risk factors included in the analysis. No indication for rs4287174-by-income interaction was observed. Conclusion: Results imply that genetic effects of the CRP locus are modified by education as an indicator of life course SEP.

A SARS-CoV-2 outbreak at a meat processing plant (MPP) in the German district of Gütersloh accounted for 18% of Germany’s SARS-CoV-2 cases in June 2020 and was subject of intense public interest, including the speculation that the outbreak strain may have been imported by foreign MPP workers. We sequenced the SARS-CoV-2 genomes of 1,438 SARS-CoV-2 samples collected from Gütersloh MPP workers for serial diagnostic testing and screening purposes (“outbreak samples”; approximate case coverage 68%) and of 157 samples collected from Gütersloh-area cases for routine diagnostic purposes (“community samples”). Greater than 98% of outbreak samples carried the outbreak-associated strain, defined by eight mutations and lineage B.1.329, confirming the overall clonality of the outbreak and showing that potential secondary introductions of other viral lineages had an at most limited role. Of fifteen viral sub-lineages detected in early outbreak-associated samples sequenced by another study, only one showed substantial persistence into the peak outbreak period, suggesting that transmission dynamics within the MPP were influenced by bottlenecks and superspreading-like patterns. While the detection of B.1.329 in community samples peaked during the outbreak, it was found to be present in community samples between March and September 2020, with the first exact matches to the outbreak strain appearing in April 2020. We found no epidemiological connections between early B.1.329-carrying community cases and the MPP, and a GISAID search for B.1.329 did not identify any samples collected outside of Germany. The outbreak strain was therefore likely circulating within the community before the outbreak and there was no indication of importation by MPP workers. Our study demonstrates how large-scale viral genome sequencing can contribute to the investigation of outbreaks and inform public discourse.

•Receptor density and gene expression data are from the same human hippocampal tissue.•Significant differences in receptor density only found in metabotropic receptors.•Significant differences in RNA expression mostly pertained ionotropic receptors.•Complex correlation between receptor densities and corresponding gene expressions. Neurotransmitter receptors are key molecules in signal transmission, their alterations are associated with brain dysfunction. Relationships between receptors and their corresponding genes are poorly understood, especially in humans. We combined in vitro receptor autoradiography and RNA sequencing to quantify, in the same tissue samples (7 subjects), the densities of 14 receptors and expression levels of their corresponding 43 genes in the Cornu Ammonis (CA) and dentate gyrus (DG) of human hippocampus. Significant differences in receptor densities between both structures were found only for metabotropic receptors, whereas significant differences in RNA expression levels mostly pertained ionotropic receptors. Receptor fingerprints of CA and DG differ in shapes but have similar sizes; the opposite holds true for their “RNA fingerprints”, which represent the expression levels of multiple genes in a single area. In addition, the correlation coefficients between receptor densities and corresponding gene expression levels vary widely and the mean correlation strength was weak-to-moderate. Our results suggest that receptor densities are not only controlled by corresponding RNA expression levels, but also by multiple regionally specific post-translational factors.

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10−9, OR = 1.36, 95% CI = [1.23–1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10−9, OR = 1.24, 95% CI = [1.15–1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.

Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis -regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis -meQTLs at 14,118 CpG methylation sites and cis -eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal cis -meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis -acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis -acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders. Most SNPs are located in non-coding genomic regions and their function remains elusive. Here, the authors perform a genome-wide scan of expression and DNA methylation quantitative trait loci in human hippocampal tissue to provide a resource for the functional interpretation of SNPs in brain disorders.

Culture medium of mesenchymal stromal cells (MSCs) is usually supplemented with either human platelet lysate (HPL) or fetal calf serum (FCS). Many studies have demonstrated that proliferation and cellular morphology are affected by these supplements – it is therefore important to determine if they favor outgrowth of different subpopulations and thereby impact on the heterogeneous composition of MSCs. We have isolated and expanded human bone marrow-derived MSCs in parallel with HPL or FCS and demonstrated that HPL significantly increases proliferation and leads to dramatic differences in cellular morphology. Remarkably, global DNA-methylation profiles did not reveal any significant differences. Even at the transcriptomic level, there were only moderate changes in pairwise comparison. Furthermore, the effects on proliferation, cytoskeletal organization, and focal adhesions were reversible by interchanging to opposite culture conditions. These results indicate that cultivation of MSCs with HPL or FCS has no systematic bias for specific cell types.

Background: Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene–environment interactions can change the methylation status in the brain, and accumulation of these epigenetic changes over a lifespan may be co-responsible for a neurodegenerative disease like Parkinson’s disease, which that is characterised by a late onset in life. Aims: To determine epigenetic modifications in the brains of Parkinson’s disease patients. Patients and Methods: DNA methylation patterns were compared in the cortex tissue of 14 male PD patients and 10 male healthy individuals using the Illumina Methylation 450 K chip. Subsequently, DNA methylation of candidate genes was evaluated using bisulphite pyrosequencing, and DNA methylation of cytochrome P450 2E1 (CYP2E1) was characterized in DNA from blood mononuclear cells (259 PD patients and 182 healthy controls) and skin fibroblasts (10 PD patients and 5 healthy controls). Protein levels of CYP2E1 were analysed using Western blot in human cortex and knock-out mice brain samples. Results: We found 35 hypomethylated and 22 hypermethylated genes with a methylation M-value difference >0.5. Decreased methylation of cytochrome P450 2E1 (CYP2E1) was associated with increased protein levels in PD brains, but in peripheral tissues, i.e., in blood cells and skin fibroblasts, DNA methylation of CYP2E1 was unchanged. In CYP2E1 knock-out mice brain alpha-synuclein (SNCA) protein levels were down-regulated compared to wild-type mice, whereas treatment with trichloroethylene (TCE) up-regulated CYP2E1 protein in a dose-dependent manner in cultured cells. We further identified an interconnected group of genes associated with oxidative stress, such as Methionine sulfoxide reductase A (MSRA) and tumour protein 73 (TP73) in the brain, which again were not paralleled in other tissues and appeared to indicate brain-specific changes. Conclusions: Our study revealed surprisingly few dysmethylated genes in a brain region less affected in PD. We confirmed hypomethylation of CYP2E1.

Background To examine the association between lipoprotein(a) (Lp(a)) levels, LPA (rs10455872 and rs3798220) and IL1F9 (rs13415097) single nucleotide polymorphisms (SNPs) with coronary artery calcification (CAC), an important predictor for coronary artery disease (CAD). Methods We used data from 3799 (mean age ± SD: 59.0 ± 7.7 years, 47.1% men) Heinz Nixdorf Recall study participants. We applied linear regression models to explore the relation between the log-transformed Lp(a) levels and LPA and IL1F9 SNPs with log e (CAC + 1). The association between the SNPs and log-transformed Lp(a) levels was further assessed using linear regression. The models were adjusted for age and sex (Model 1) and additionally for Lp(a) levels (Model 2). Results We observed a statistically significant association between log-transformed Lp(a) levels and CAC (Model 1: beta per log-unit increase in Lp(a) levels = 0.11; 95% confidence interval [95% CI] [0.04; 0.18], p =  0.002). Furthermore, the LPA SNP rs10455872 showed a statistically significant association with CAC (Model 1: beta per allele = 0.37 [0.14; 0.61], p =  0.002). The association between rs10455872 and CAC was attenuated after adjustment for Lp(a) levels (Model 2: beta per allele = 0.26 [− 0.01; 0.53], p =  0.06). Both LPA SNPs also showed a statistically significant association with Lp(a) levels (Model 1: beta rs10455872 per allele: 1.56 [1.46; 1.65], p <  0.0001 and beta rs3798220 per allele: 1.51 [1.33; 1.69], p <  0.0001)). The Mendelian randomization analysis showed that Lp(a) is a causal risk factor for CAC (estimate per log-unit increase in Lp(a) levels (95% CI), p : 0.27 [0.11; 0.44], p =  0.001). The IL1F9 SNP did not show any statistically significant association with Lp(a) levels or with CAC. Conclusions We provide evidence for the association of LPA rs10455872 with higher levels of Lp(a) and CAC in our study. The results of our study suggest that rs10455872, mediated by Lp(a) levels, might play a role in promoting the development of atherosclerosis leading to cardiovascular disease events.