Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network

Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits

Model-driven engineering of an openCypher engine: using graph queries to compile graph queries

Graph database systems are increasingly adapted for storing and processing heterogeneous network-like datasets. Many challenging applications with near real-time requirements - such as financial fraud detection, on-the-fly model validation and root cause analysis - can be formalised as graph problems and tackled with graph databases efficiently. However, as no standard graph query language has yet emerged, users are subjected to the possibility of vendor lock-in. The openCypher group aims to define an open specification for a declarative graph query language. However, creating an openCypher-compatible query engine requires significant research and engineering efforts. Meanwhile, model-driven language workbenches support the creation of domain-specific languages by providing high-level tools to create parsers, editors and compilers. In this paper, we present an approach to build a compiler and optimizer for openCypher using model-driven technologies, which allows developers to define declarative optimization rules

Constraints and conditions: drivers for design processes

A theory of design that is useful for understanding and improving design processes in industry should account for both the similarities and the differences between processes, across products, companies and industries, and indicate how they can be influenced. Design processes are shaped by the constraints the product and the process need to meet and the context in which development process takes place. This chapter advocates the incremental development of design theory by identifying the major causal drivers that influence how designing is done, and constructing and revising causal stories for how they affect design. A number of important drivers are identified and related to different types of constraints on products and processes; one important factor is whether or not conformity to requirements can be assessed objectively

The diagnosis and management of a patient with acute pyelonephritis

Lower urinary tract infections account for more than 224 000 hospital admissions each year and nearly all of these have the pathophysiological possibility to develop into pyelonephritis, known clinically as an upper urinary tract infection. Acute pyelonephritis is characterised by inflammation of the renal parenchyma caused by bacteriuria ascending from the bladder, up the ureters to the kidneys. Effective history taking, combined with refined physical examination skills, are the two most powerful tools to differentiate upper and lower urinary tract infections as well as assisting the practitioner to exclude other differential diagnoses. Utilisation of these skills by the practitioner, together with the recognised presenting symptom triad of flank pain, fever and nausea in this case study, enabled the diagnosis of acute pyelonephritis to be given.N/

Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia

OBJECTIVE: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. DESIGN: We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations. RESULTS: Two correlated SNPs--rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. CONCLUSIONS: This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants

Genetic studies of body mass index yield new insights for obesity biology

Note: A full list of authors and affiliations appears at the end of the article. Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.</p