14 Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R 2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Organotypic 3D Models of the Ovarian Cancer Tumor Microenvironment

Ovarian cancer progression involves multifaceted and variable tumor microenvironments (TMEs), from the in situ carcinoma in the fallopian tube or ovary to dissemination into the peritoneal cavity as single cells or spheroids and attachment to the mesothelial-lined surfaces of the omentum, bowel, and abdominal wall. The TME comprises the tumor vasculature and lymphatics (including endothelial cells and pericytes), in addition to mesothelial cells, fibroblasts, immune cells, adipocytes and extracellular matrix (ECM) proteins. When generating 3D models of the ovarian cancer TME, researchers must incorporate the most relevant stromal components depending on the TME in question (e.g., early or late disease). Such complexity cannot be captured by monolayer 2D culture systems. Moreover, immortalized stromal cell lines, such as mesothelial or fibroblast cell lines, do not always behave the same as primary cells whose response in functional assays may vary from donor to donor; 3D models with primary stromal cells may have more physiological relevance than those using stromal cell lines. In the current review, we discuss the latest developments in organotypic 3D models of the ovarian cancer early metastatic microenvironment. Organotypic culture models comprise two or more interacting cell types from a particular tissue. We focus on organotypic 3D models that include at least one type of primary stromal cell type in an ECM background, such as collagen or fibronectin, plus ovarian cancer cells. We provide an overview of the two most comprehensive current models—a 3D model of the omental mesothelium and a microfluidic model. We describe the cellular and non-cellular components of the models, the incorporation of mechanical forces, and how the models have been adapted and utilized in functional assays. Finally, we review a number of 3D models that do not incorporate primary stromal cells and summarize how integration of current models may be the next essential step in tackling the complexity of the different ovarian cancer TMEs

Using timed up-and-go to identify frail members of the older population

Fried's definition of frailty is widely used but its measurement is problematic. Timed up-and-go (TUG) is a simple measure of mobility that may be a useful proxy for frailty. Here, we describe the distribution of frailty and TUG in the older population of Ireland and discuss the extent to which TUG identifies the frail and prefrail populations

Variance between walking speed and neuropsychological test scores during three gait tasks across the irish longitudinal study on aging (TILDA) dataset

This study investigated the relationship between neuropsychological test scores and gait speed in three gait tasks using baseline cross-sectional data from 4694 healthy adults (54% women, age (mean±sd) 62.4±8.2) from The Irish Longitudinal study on Aging (TiLDA). Global cognition, short term memory, speed of processing, executive function and sustained attention were measured by a detailed battery of neuropsychological tests. Gait speed was recorded from a GaitRite™ pressure sensing mat during a single walk and two dual walking tasks; dual cognitive walk (alternate letters) and dual motor walk (carrying a glass of water). Correlations between neuropsychological test scores and the three gait speed outcomes were investigated using univariate and multiple linear regressions models; firstly adjusting for age, gender, height, education and depression only and then including all neuropsychological test scores in the same regression model and adjusting as previously. It was found that short term memory, speed of processing and attention were significantly correlated with gait speed in all three gait conditions, with global cognition and executive function also significantly correlated with gait speed in the dual cognitive walk. The nature and complexity of the task performed affected gait speed with the addition of the cognitive task while walking causing a larger reduction in gait speed than the addition of the motor task. This indicates that for this healthy nationally representative population sample there is a link between neural processes involved in movement and cognition and this association differs depending on the gait task performed

Oscillometric measure of blood pressure detects association between orthostatic hypotension and depression in population based study of older adults

Background: White matter hyperintensities may contribute to depression by disrupting neural connections among brain regions that regulate mood. Orthostatic hypotension (OH) may be a risk factor for white matter hyperintensities and accumulating evidence, although limited suggests it may play a role in the development of late-life depression. The aim of this study was to examine the relationship between an oscillometric measure of orthostatic hypotension and depression in population based sample of older adults.  Methods: We analysed data on adults aged 60 and over from the first wave of The Irish Longitudinal Study on Ageing (TILDA). Depression was assessed using the Center for Epidemiologic Studies – Depression (CES–D) scale and OH was assessed by a sit-to-stand orthostatic stress test; two seated blood pressure measurements were followed by a single standing blood pressure measurement. Participants self reported whether they felt dizzy, light-headed or unsteady on standing. Results Participants with symptomatic OH (SOH, n=20) had the highest mean CES-D score (mean 8.6, SE 1.6) when compared to participants with asymptomatic OH (AOH) (mean 5.6, SE .48) and participants with no OH (mean 5.2, SE .14) and this difference was significant for both comparisons (p<0.001). Linear regression analysis adjusted for socio-demographic and clinical characteristics showed that SOH was associated with higher CES-D scores (unstandardised B coefficient = 2.24; 95% CI .301 - 4.79; p =0.05) compared to participants without OH. AOH was not associated with higher CES-D scores (unstandardised B coefficient =.162; 95% CI -.681, 1.00; p= 0.70).  Conclusions: Symptomatic orthostatic hypotension is associated with depression in older adults and needs to be considered in studies examining the relationship between vascular disease and depression in older adults

Factors affecting continuous beat-to-beat orthostatic blood pressure response in community-dwelling older adults

To examine the effect of age, time of day, the timing of medication and food ingestion on orthostatic blood pressure response (OBP) in community-dwelling adults