133 research outputs found
A case report and genetic characterization of a massive acinic cell carcinoma of the parotid with delayed distant metastases.
We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure
Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure
BR-squared: a practical solution to the winner’s curse in genome-wide scans
The detrimental effects of the winner’s curse, including overestimation of the genetic effects of associated variants and underestimation of sufficient sample sizes for replication studies are well-recognized in genome-wide association studies (GWAS). These effects can be expected to worsen as the field moves from GWAS into whole genome sequencing. To date, few studies have reported statistical adjustments to the naive estimates, due to the lack of suitable statistical methods and computational tools. We have developed an efficient genome-wide non-parametric method that explicitly accounts for the threshold, ranking, and allele frequency effects in whole genome scans. Here, we implement the method to provide bias-reduced estimates via bootstrap re-sampling (BR-squared) for association studies of both disease status and quantitative traits, and we report the results of applying BR-squared to GWAS of psoriasis and HbA1c. We observed over 50% reduction in the genetic effect size estimation for many associated SNPs. This translates into a greater than fourfold increase in sample size requirements for successful replication studies, which in part explains some of the apparent failures in replicating the original signals. Our analysis suggests that adjusting for the winner’s curse is critical for interpreting findings from whole genome scans and planning replication and meta-GWAS studies, as well as in attempts to translate findings into the clinical setting
A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose
Refurbishment options to decarbonise a 1960s public office building by 2050s
Climate change and the subsequent impact this has on carbon emissions for buildings has shown great concern for the industry. With over 1.35 million non-domestic buildings at least over 25 years old; the need for more practical refurbishment strategies in order to decarbonise and future-proof the old building stock against climate change is vital. The aim of this paper is to explore more sustainable, economic and less-disruptive refurbishment approaches for an air conditioned building as efficient future weather mitigation measures. Particular emphasis was placed on the evaluation of the carbon reductions associated with the best-suited approaches under two future climatic scenarios, 2030 & 2050.
A building simulation model of a public office building has been developed to assess the current energy performance as well as the predicted future energy performance for two refurbishment strategies. These strategies are adaptive thermal control and fabric modification. A reduction in carbon emissions, of 7.5%, results from applying adaptive heating and cooling set points to the model with a current weather data scenario. This reduces to 6.8% in 2030 and 5.3% in 2050. The potential savings are most significant for the current climate scenario and then reduce for the 2030 and 2050 scenarios largely because of an elevation in heating set points. In terms of cooling, an upper limit to the cooling set point of 26°C prevents meaningful differentiation between the 2030 and 2050 adaptive cooling set points but is necessary due to the lack of opportunities for building occupants to adapt their conditions. There is scope for research to be carried out into the application of adaptive set points for existing buildings. Some work has been carried out on the cooling scenario but little appears to have been done for heating as of yet. Given that this could be retrofitted into BMS systems, it is a potential option to reduce building carbon emissions with minimal cost for buildings with centralised systems. For the fabric modification, a significant reduction in carbon emissions was achieved by the use of composite panels to replace much of the glazing. This resulted in a significant improvement in building performance but at a significant investment cost
Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD
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<i>De Novo</i> and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects
Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk
Fuel poverty-induced ‘prebound effect’ in achieving the anticipated carbon savings from social housing retrofit
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