Exome Sequencing and Complex Disease: Practical Aspects of Rare Variant Association Studies

Genetic association and linkage studies can provide insights into complex disease biology, guiding the development of new diagnostic and therapeutic strategies. Over the past decade, genetic association studies have largely focused on common, easy to measure genetic variants shared between many individuals. These common variants typically have subtle functional consequence and translating the resulting association signals into biological insights can be challenging. In the last few years, exome sequencing has emerged as a cost-effective strategy for extending these studies to include rare coding variants, which often have more marked functional consequences. Here, we provide practical guidance in the design and analysis of complex trait association studies focused on rare, coding variants

The generality of the GUGA MRCI approach in COLUMBUS for treating complex quantum chemistry

The core part of the program system COLUMBUS allows highly efficient calculations using variational multireference (MR) methods in the framework of configuration interaction with single and double excitations (MR-CISD) and averaged quadratic coupled-cluster calculations (MR-AQCC), based on uncontracted sets of configurations and the graphical unitary group approach (GUGA). The availability of analytic MR-CISD and MR-AQCC energy gradients and analytic nonadiabatic couplings for MR-CISD enables exciting applications including, e.g., investigations of π-conjugated biradicaloid compounds, calculations of multitudes of excited states, development of diabatization procedures, and furnishing the electronic structure information for on-the-fly surface nonadiabatic dynamics. With fully variational uncontracted spin-orbit MRCI, COLUMBUS provides a unique possibility of performing high-level calculations on compounds containing heavy atoms up to lanthanides and actinides. Crucial for carrying out all of these calculations effectively is the availability of an efficient parallel code for the CI step. Configuration spaces of several billion in size now can be treated quite routinely on standard parallel computer clusters. Emerging developments in COLUMBUS, including the all configuration mean energy multiconfiguration self-consistent field method and the graphically contracted function method, promise to allow practically unlimited configuration space dimensions. Spin density based on the GUGA approach, analytic spin-orbit energy gradients, possibilities for local electron correlation MR calculations, development of general interfaces for nonadiabatic dynamics, and MRCI linear vibronic coupling models conclude this overview

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Biomass Production of Herbaceous Energy Crops in the United States: Field Trial Results and Yield Potential Maps from the Multiyear Regional Feedstock Partnership

Current knowledge of yield potential and best agronomic management practices for perennial bioenergy grasses is primarily derived from small‐scale and short‐term studies, yet these studies inform policy at the national scale. In an effort to learn more about how bioenergy grasses perform across multiple locations and years, the U.S. Department of Energy (US DOE)/Sun Grant Initiative Regional Feedstock Partnership was initiated in 2008. The objectives of the Feedstock Partnership were to (1) provide a wide range of information for feedstock selection (species choice) and management practice options for a variety of regions and (2) develop national maps of potential feedstock yield for each of the herbaceous species evaluated. The Feedstock Partnership expands our previous understanding of the bioenergy potential of switchgrass, Miscanthus, sorghum, energycane, and prairie mixtures on Conservation Reserve Program land by conducting long‐term, replicated trials of each species at diverse environments in the U.S. Trials were initiated between 2008 and 2010 and completed between 2012 and 2015 depending on species. Field‐scale plots were utilized for switchgrass and Conservation Reserve Program trials to use traditional agricultural machinery. This is important as we know that the smaller scale studies often overestimated yield potential of some of these species. Insufficient vegetative propagules of energycane and Miscanthus prohibited farm‐scale trials of these species. The Feedstock Partnership studies also confirmed that environmental differences across years and across sites had a large impact on biomass production. Nitrogen application had variable effects across feedstocks, but some nitrogen fertilizer generally had a positive effect. National yield potential maps were developed using PRISM‐ELM for each species in the Feedstock Partnership. This manuscript, with the accompanying supplemental data, will be useful in making decisions about feedstock selection as well as agronomic practices across a wide region of the country

A High-Throughput Screen for Tuberculosis Progression

One-third of the world population is infected with Mycobacterium tuberculosis and multi-drug resistant strains are rapidly evolving. The noticeable absence of a whole organism high-throughput screening system for studying the progression of tuberculosis is fast becoming the bottleneck in tuberculosis research. We successfully developed such a system using the zebrafish Mycobacterium marinum infection model, which is a well-characterized model for tuberculosis progression with biomedical significance, mimicking hallmarks of human tuberculosis pathology. Importantly, we demonstrate the suitability of our system to directly study M. tuberculosis, showing for the first time that the human pathogen can propagate in this vertebrate model, resulting in similar early disease symptoms to those observed upon M. marinum infection. Our system is capable of screening for disease progression via robotic yolk injection of early embryos and visual flow screening of late-stage larvae. We also show that this system can reliably recapitulate the standard caudal vein injection method with a throughput level of 2,000 embryos per hour. We additionally demonstrate the possibility of studying signal transduction leading to disease progression using reverse genetics at high-throughput levels. Importantly, we use reference compounds to validate our system in the testing of molecules that prevent tuberculosis progression, making it highly suited for investigating novel anti-tuberculosis compounds in vivo