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Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Background Several small molecule corrector and potentiator drugs have recently been licensed for Cystic Fibrosis (CF) therapy. However, other aspects of the disease, especially inflammation, are less effectively treated by these drugs. We hypothesized that small molecule drugs could function either alone or as an adjuvant to licensed therapies to treat these aspects of the disease, perhaps emulating the effects of gene therapy in CF cells. The cardiac glycoside digitoxin, which has been shown to inhibit TNFα/NFκB signaling in CF lung epithelial cells, may serve as such a therapy. Methods IB3–1 CF lung epithelial cells were treated with different Vertex (VX) drugs, digitoxin, and various drug mixtures, and ELISA assays were used to assess suppression of baseline and TNFα-activated secretion of cytokines and chemokines. Transcriptional responses to these drugs were assessed by RNA-seq and compared with gene expression in AAV-[ wildtype ]CFTR-treated IB3–1 (S9) cells. We also compared in vitro gene expression signatures with in vivo data from biopsied nasal epithelial cells from digitoxin-treated CF patients. Results CF cells exposed to digitoxin exhibited significant suppression of both TNFα/NFκB signaling and downstream secretion of IL-8, IL-6 and GM-CSF, with or without co-treatment with VX drugs. No evidence of drug-drug interference was observed. RNA-seq analysis showed that gene therapy-treated CF lung cells induced changes in 3134 genes. Among these, 32.6% were altered by digitoxin treatment in the same direction. Shared functional gene ontology themes for genes suppressed by both digitoxin and gene therapy included inflammation (84 gene signature), and cell-cell interactions and fibrosis (49 gene signature), while genes elevated by both were enriched for epithelial differentiation (82 gene signature). A new analysis of mRNA data from digitoxin-treated CF patients showed consistent trends in expression for genes in these signatures. Conclusions Adjuvant gene therapy-emulating activities of digitoxin may contribute to enhancing the efficacy of currently licensed correctors and potentiators in CF patients.

A correction to this paper has been published: https://doi.org/10.1007/s00401-021-02309-z

Post-traumatic stress disorder (PTSD) is psychiatric disease, which can occur following exposure to traumatic events. PTSD may be acute or chronic, and can have a waxing and waning course of symptoms. It has been hypothesized that proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) or plasma might be mediators of the psychophysiological mechanisms relating a history of trauma exposure to changes in behavior and mental health disorders, and medical morbidity. Here we test the cytokine/chemokine hypothesis for PTSD by examining levels of 17 classical cytokines and chemokines in CSF, sampled at 0900 hours, and in plasma sampled hourly for 24 h. The PTSD and healthy control patients are from the NIMH Chronic PTSD and healthy control cohort, initially described by Bonne et al. (2011), in which the PTSD patients have relatively low comorbidity for major depressive disorder (MDD), drug or alcohol use. We find that in plasma, but not CSF, the bivariate MCP4 (CCL13)/ MCP1(CCL2) ratio is ca. twofold elevated in PTSD patients compared with healthy controls. The MCP-4/MCP-1 ratio is invariant over circadian time, and is independent of gender, body mass index or the age at which the trauma was suffered. By contrast, MIP-1β is a candidate biomarker for PTSD only in females, whereas TARC is a candidate biomarker for PTSD only in males. It remains to be discovered whether these disease-specific differences in circadian expression for these specific immune signaling molecules are biomarkers, surrogates, or drivers for PTSD, or whether any of these analytes could contribute to therapy.

This systematic literary review investigates if an association between Sami dietary habits and cardiometabolic outcomes exists, and examines the dietary characteristics and cardiometabolic status of the Sami population. Included were all articles assessing Sami dietary habits and cardiometabolic disease or risk factors. Embase, Medline and SweMed were searched on 26 September 2019 and articles were screened for eligibility in October 2019. Data were extracted according to Moose Guidelines and the Newcastle Ottawa Scale (NOS) was used to assess risk of bias. The initial search generated 4,195 articles in total. Nine articles met all inclusion criteria. Two were cohort studies and seven were cross-sectional. Rating by NOS ranked from 2/7 to 8/9 stars. The studies were largely descriptive and only few had results regarding a direct association between Sami dietary habits and cardiometabolic outcomes. The findings demonstrated no association between consumption of certain Sami food items and blood-lipids or mortality from CVD/CHD. A higher intake of fat, protein, reindeer-meat and coffee and a slightly lower blood pressure and mortality from CVD/CHD was seen among Sami compared with non-Sami. The limited amount and descriptive nature of the eligible articles indicate that resaerch within the fielt is limited. Thus, additional longitudinal studies are suggested.

Twin pairs discordant for disease may help elucidate the epigenetic mechanisms and causal environmental factors in disease development and progression. To obtain the numbers of pairs, especially monozygotic (MZ) twin pairs, necessary for in-depth studies while also allowing for replication, twin studies worldwide need to pool their resources. The Discordant Twin (DISCOTWIN) consortium was established for this goal. Here, we describe the DISCOTWIN Consortium and present an analysis of type 2 diabetes (T2D) data in nearly 35,000 twin pairs. Seven twin cohorts from Europe (Denmark, Finland, Norway, the Netherlands, Spain, Sweden, and the United Kingdom) and one from Australia investigated the rate of discordance for T2D in same-sex twin pairs aged 45 years and older. Data were available for 34,166 same-sex twin pairs, of which 13,970 were MZ, with T2D diagnosis based on self-reported diagnosis and medication use, fasting glucose and insulin measures, or medical records. The prevalence of T2D ranged from 2.6% to 12.3% across the cohorts depending on age, body mass index (BMI), and national diabetes prevalence. T2D discordance rate was lower for MZ (5.1%, range 2.9–11.2%) than for same-sex dizygotic (DZ) (8.0%, range 4.9–13.5%) pairs. Across DISCOTWIN, 720 discordant MZ pairs were identified. Except for the oldest of the Danish cohorts (mean age 79), heritability estimates based on contingency tables were moderate to high (0.47–0.77). From a meta-analysis of all data, the heritability was estimated at 72% (95% confidence interval 61–78%). This study demonstrated high T2D prevalence and high heritability for T2D liability across twin cohorts. Therefore, the number of discordant MZ pairs for T2D is limited. By combining national resources, the DISCOTWIN Consortium maximizes the number of discordant MZ pairs needed for in-depth genotyping, multi-omics, and phenotyping studies, which may provide unique insights into the pathways linking genes to the development of many diseases.

The aim of this study was to compare health-related quality of life (HQoL) in adults with dermatomyositis (DM) or polymyositis (PM) with a healthy control group and to assess whether muscle strength was associated with HQoL in patients with DM or PM. A cross-sectional study was performed and included 75 patients with DM or PM and 48 healthy controls. HQoL was assessed by the Short Form 36 questionnaire (SF-36). Muscle strength of the patients was assessed using the Manual Muscle Test-8 (MMT8). Covariables and possible confounding factors were collected by validated tools. Associations were determined in multiple linear regression models. The patients had significantly lower HQoL than the control group in both the physical component summary score (PCS) and the mental component summary score (MCS). Thus, the PCS-difference between groups was 32% ( p  < 0.001), whereas the MCS-difference was 14% ( p  < 0.001). Muscle strength was associated with one domain in the patients; Physical Function (β = 1.2; 95% confidence interval 0.37 to 2.1). No statistically significant associations were found between muscle strength and HQoL in the remaining domains. Patients with DM or PM have reduced HQoL compared to healthy controls. Notably, muscle strength was associated with scores of the domain reflecting perceived physical function in patients. These findings corroborate the validity of including selected patient reported outcomes in the evaluation and monitoring of patients with DM or PM.

Traumatic brain injury (TBI) results from a primary injury that impacts the brain in a spatially-dependent manner. Here we investigated the topographical relationship of early transcriptional responses to a single, focal TBI in mice by controlled cortical impact (CCI). Guided by the presence of the anterior commissure (AC) in coronal sections at the rostro-caudal point of impact, we compared gene expression changes in the neocortex (CTX) and corpus callosum-external capsule (CC-EC), striatum (STR) and AC. Injury-induced gene expression changes were detected in the CTX, CC-EC and STR but not AC and were principally segregated based on cytoarchitecture, and secondarily by proximity to the site of impact. Additionally, unbiased spatial clustering revealed a positive relationship between proximity to the impact and the number of acutely differentially expressed genes within the laminar CTX. Gene pathways for interferon gamma response and for leukocyte-mediated migration and immunity were acutely enhanced across the injured CTX, CC-EC and STR. Within 1-week post-injury, transcriptional responses to injury in the CTX and CC-EC included gene pathways for adaptive T- and B-cell mediated immunity, whereas gene expression changes in the STR were largely resolved. Next, we examined the effects of systemic depletion of neutrophils and monocytes on spatial gene expression changes in the injured brain. This led to the upregulation of gene pathways functioning in synaptic transmission and an alternating down- and then upregulation of genes functioning in ribosomal messenger RNA translation and aerobic metabolism in mitochondria. These data suggest infiltrating neutrophils and monocytes play an evolving, multifaceted role in modulating the metabolic, transcriptional, and synaptic activity of brain tissue post-injury.

Background and Objectives: Stress can overload adaptive mechanisms, leading to epigenetic effects harmful to health. Research on the reversal of these effects is in its infancy. Early results suggest some meditation techniques have health benefits that grow with repeated practice. This study focused on possible transcriptomic effects of 38 years of twice-daily Transcendental Meditation® (TM®) practice. Materials and Methods: First, using Illumina® BeadChip microarray technology, differences in global gene expression in peripheral blood mononuclear cells (PBMCs) were sought between healthy practitioners and tightly matched controls (n = 12, age 65). Second, these microarray results were verified on a subset of genes using quantitative polymerase chain reaction (qPCR) and were validated using qPCR in larger TM and control groups (n = 45, age 63). Bioinformatics investigation employed Ingenuity® Pathway Analysis (IPA®), DAVID, Genomatix, and R packages. Results: The 200 genes and loci found to meet strict criteria for differential expression in the microarray experiment showed contrasting patterns of expression that distinguished the two groups. Differential expression relating to immune function and energy efficiency were most apparent. In the TM group, relative to the control, all 49 genes associated with inflammation were downregulated, while genes associated with antiviral and antibody components of the defense response were upregulated. The largest expression differences were shown by six genes related to erythrocyte function that appeared to reflect a condition of lower energy efficiency in the control group. Results supporting these gene expression differences were obtained with qPCR-measured expression both in the well-matched microarray groups and in the larger, less well-matched groups. Conclusions: These findings are consistent with predictions based on results from earlier randomized trials of meditation and may provide evidence for stress-related molecular mechanisms underlying reductions in anxiety, post-traumatic stress disorder (PTSD), cardiovascular disease (CVD), and other chronic disorders and diseases.

PurposeThis study assessed the feasibility of telephone follow-up consultations (TC) using an online data sharing and editing function (Airview™), as alternative to standard out-clinic follow-up consultations (SC) on adherence to continuous positive airway pressure (CPAP) in obstructive sleep apnea (OSA) patients. Furthermore, we investigated compliance to follow-up consultations and examined potential influencing factors, including baseline AHI (apnea–hypopnea-index), age, and distance from home to the hospital on consultation compliance.MethodsTwo hundred OSA patients, with AHI ≥ 5 were randomly assigned (1:1) to receive TC or SC with follow-up after one month and 12 month of CPAP initiation. Adherence goal was defined as achieving ≥ 4 h of CPAP use daily in 70% of the days in a 365-days period.ResultsThe proportion of participants achieving CPAP adherence was non-significantly lower in the TC group compared to the SC group (TC: 30% versus SC: 36%, adjusted OR 0.84, p = 0.59). Of participants who completed the study, the TC group had a significant average of 107 min less use of CPAP compared to the SC group (p = 0.048). However, a higher proportion of participants was compliant to consultations in the TC group. The only influencing factor found was increasing baseline AHI, which might be a predictor for compliance to consultations and adherence to CPAP therapy.ConclusionTC might serve as substitute for SC in some part of the OSA population. If TC becomes a part of CPAP therapy management, it is important to consider patient characteristics and treatment-related issues to prevent decline in adherence.