Dementias Platform UK: Bringing genetics into life.

INTRODUCTION: The Dementias Platform UK (DPUK) Data Portal is a data repository bringing together a wide range of cohorts. Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and an overlapping genetic component that is poorly understood. The DPUK collection of independent cohorts can facilitate research in neurodegeneration by combining their genetic and phenotypic data. METHODS: For genetic data processing, pipelines were generated to perform quality control analysis, genetic imputation, and polygenic risk score (PRS) derivation with six genome-wide association studies of neurodegenerative diseases. Pipelines were applied to five cohorts. DISCUSSION: The data processing pipelines, research-ready imputed genetic data, and PRS scores are now available on the DPUK platform and can be accessed upon request though the DPUK application process. Harmonizing genome-wide data for multiple datasets increases scientific opportunity and allows the wider research community to access and process data at scale and pace.

Genome sequencing projects reveal new insights into the mammalian Gonadotropin-releasing Hormone II system.

The type II gonadotropin-releasing hormone (GnRH-II) was first discovered in chicken (Gallus gallus) brain and then shown to be present in many vertebrates. Indeed, its structure is conserved unchanged throughout vertebrate evolution from teleost fish through to mammals suggesting a crucial function. Yet the functional significance has been largely unexplored. Studies in comparative endocrinology show that the GnRH-II system is differentially functional in mammalian species. Intact GnRH-II neuropeptide and receptor genes (GnRH2 and GnRH receptor 2 GnRHR2) occur in marmoset monkeys (Callithrix jacchus), musk shrews (Suncus murinus) and pigs (Sus scrofa). However, one or other or both of these genes are inactivated in other species, where mutations or remnants affecting GnRH2 neuropeptide and/or type II GnRHR exons are retained in conserved genomic loci. New data from DNA sequencing projects facilitate extensive analysis of species-specific variation in these genes. Here, we describe GnRH2 and GnRHR2 genes spanning a collection of 21 taxonomic orders, encompassing around 140 species from Primates, Scandentia, Eulipotyphla, Rodentia, Lagomorpha, Artiodactyla, Carnivora, Perissodactyls, Pholidota, Chiroptera, Afrotheria, Xenarthra and Marsupialia. Intact coding exons for both GnRH2 and GnRHR2 occur in monkeys, tree shrews, shrews, moles, hedgehogs, several rodents (degu, kangaroo-rat, pocket mouse), pig, pecarry and warthog, camels and alpaca, bears, Weddell seal, hyena, elephant, aardvark and marsupials. Inactivating mutations affecting GnRH2 and GnRHR2, some located at conserved sites within exons, occur in species of primates, most rodents, lagomorphs, bovidae, cetaceans, felidae, canidae and other carnivora, pangolins, most bats, armadillo, brushtail and echidna. A functional GnRH-II system appears retained within several taxonomic families of mammals, but intact retention does not extend to whole taxonomic orders. Defining how endogenous GnRH-II neuropeptide operates in different mammals may afford functional insight into its actions in the brain, especially as, unlike the type I GnRH system, it is expressed in the mid brain and not the hypothalamus.

Repair of lymphoperitoneal fistulae for chylous ascites following robotic-assisted partial nephrectomy: Anatomic foundation for left-sided predominance following renal surgery.

Chylous ascites (CA) is a rare complication following renal surgery. Here we present the case of a 28-year-old female who developed CA after a robotic left partial nephrectomy. After failing conservative management, she underwent successful robotic-assisted diagnostic laparoscopy and ligation of lymphoperitoneal fistulae. The higher incidence of CA after left versus right-sided renal surgery may be explained by the para-aortic drainage of the intestinal lymphatic channels. Surgical intervention should be considered when conservative management fails.

Homes Heat Health protocol: an observational cohort study measuring the effect of summer temperatures on sleep quality.

INTRODUCTION: Quality sleep is essential to our health and well-being. Summertime temperatures in the bedrooms of homes in temperate climates are increasing, especially in city apartments. There is very little empirical evidence of the effect of temperature on sleep when people are sleeping in their own bedroom. The Homes Heat Health project seeks to develop a measurable definition of temperature-related sleep disturbance and the effects on health, and so produce a credible criterion for identifying overheating in new and existing homes. METHODS AND ANALYSIS: A cohort of at least 95 people that live in London apartments and who are free of significant personal and health factors that could affect sleep are being recruited for an ongoing observational cohort study. A baseline questionnaire determines their customary sleep patterns and health. The geometrical form and thermal characteristics of their apartments is being recorded along with temperature, relative humidity and in some apartments CO2 levels, throughout one summer. Actigraphy records nightly sleep disturbance and every morning an app-based diary captures perceived sleep quality. Questionnaires following spells of hot weather capture changes in sleep pattern, sleep quality, and consequential health and well-being. ETHICS AND DISSEMINATION: The study protocol was approved by the Loughborough University ethics committee. The participants will receive both verbal and written information explaining the purpose of the study, what is expected of them, the incentives for participating and the feedback that will be provided. The results will be reported bi-annually to a project advisory board. Presentations will be made at conferences and the methods, intermediary and final results, in academic journals. Informing government bodies, professional organisations, construction industry representatives and housing providers is of particular importance.

An alternative method of SNP inclusion to develop a generalized polygenic risk score analysis across Alzheimer's disease cohorts.

Introduction: Polygenic risk scores (PRSs) have great clinical potential for detecting late-onset diseases such as Alzheimer's disease (AD), allowing the identification of those most at risk years before the symptoms present. Although many studies use various and complicated machine learning algorithms to determine the best discriminatory values for PRSs, few studies look at the commonality of the Single Nucleotide Polymorphisms (SNPs) utilized in these models. Methods: This investigation focussed on identifying SNPs that tag blocks of linkage disequilibrium across the genome, allowing for a generalized PRS model across cohorts and genotyping panels. PRS modeling was conducted on five AD development cohorts, with the best discriminatory models exploring for a commonality of linkage disequilibrium clumps. Clumps that contributed to the discrimination of cases from controls that occurred in multiple cohorts were used to create a generalized model of PRS, which was then tested in the five development cohorts and three further AD cohorts. Results: The model developed provided a discriminability accuracy average of over 70% in multiple AD cohorts and included variants of several well-known AD risk genes. Discussion: A key element of devising a polygenic risk score that can be used in the clinical setting is one that has consistency in the SNPs that are used to calculate the score; this study demonstrates that using a model based on commonality of association findings rather than meta-analyses may prove useful.