Investigation of genetic determinants of cognitive change in later life

Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10−8 with slope 1) and rs34743896 (p = 5 × 10−10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Interleukin-1β sequesters hypoxia inducible factor 2α to the primary cilium.

BACKGROUND: The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1β (IL-1β). We have also shown the primary cilium elongates in response to IL-1β exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2α). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling. RESULTS: Here we show, in articular chondrocytes, that IL-1β-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2α expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2α in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFα transcription activity or rescue of basal HIF-2α expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2α expression and inhibited response to prolyl hydroxylase inhibition. CONCLUSIONS: These findings suggest that ciliary sequestration of HIF-2α provides negative regulation of HIF-2α expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation

Tropical peatlands and their conservation are important in the context of COVID-19 and potential future (zoonotic) disease pandemics.

The COVID-19 pandemic has caused global disruption, with the emergence of this and other pandemics having been linked to habitat encroachment and/or wildlife exploitation. High impacts of COVID-19 are apparent in some countries with large tropical peatland areas, some of which are relatively poorly resourced to tackle disease pandemics. Despite this, no previous investigation has considered tropical peatlands in the context of emerging infectious diseases (EIDs). Here, we review: (i) the potential for future EIDs arising from tropical peatlands; (ii) potential threats to tropical peatland conservation and local communities from COVID-19; and (iii) potential steps to help mitigate these risks. We find that high biodiversity in tropical peat-swamp forests, including presence of many potential vertebrate and invertebrate vectors, combined, in places, with high levels of habitat disruption and wildlife harvesting represent suitable conditions for potential zoonotic EID (re-)emergence. Although impossible to predict precisely, we identify numerous potential threats to tropical peatland conservation and local communities from the COVID-19 pandemic. This includes impacts on public health, with the potential for haze pollution from peatland fires to increase COVID-19 susceptibility a noted concern; and on local economies, livelihoods and food security, where impacts will likely be greater in remote communities with limited/no medical facilities that depend heavily on external trade. Research, training, education, conservation and restoration activities are also being affected, particularly those involving physical groupings and international travel, some of which may result in increased habitat encroachment, wildlife harvesting or fire, and may therefore precipitate longer-term negative impacts, including those relating to disease pandemics. We conclude that sustainable management of tropical peatlands and their wildlife is important for mitigating impacts of the COVID-19 pandemic, and reducing the potential for future zoonotic EID emergence and severity, thus strengthening arguments for their conservation and restoration. To support this, we list seven specific recommendations relating to sustainable management of tropical peatlands in the context of COVID-19/disease pandemics, plus mitigating the current impacts of COVID-19 and reducing potential future zoonotic EID risk in these localities. Our discussion and many of the issues raised should also be relevant for non-tropical peatland areas and in relation to other (pandemic-related) sudden socio-economic shocks that may occur in future

Physical activity in pregnancy: a qualitative study of the beliefs of overweight and obese pregnant women

<p>Abstract</p> <p>Background</p> <p>Whilst there has been increasing research interest in interventions which promote physical activity during pregnancy few studies have yielded detailed insights into the views and experiences of overweight and obese pregnant women themselves. The qualitative study described in this paper aimed to: (i) explore the views and experiences of overweight and obese pregnant women; and (ii) inform interventions which could promote the adoption of physical activity during pregnancy.</p> <p>Methods</p> <p>The study was framed by a combined Subtle Realism and Theory of Planned Behaviour (TPB) approach. This enabled us to examine the hypothetical pathway between beliefs and physical activity intentions within the context of day to day life. The study sample for the qualitative study was chosen by stratified, purposive sampling from a previous study of physical activity measurements in pregnancy. Research participants for the current study were recruited on the basis of Body Mass Index (BMI) at booking and parity. Semi-structured, in-depth interviews were conducted with 14 overweight and obese pregnant women. Data analysis was undertaken using a Framework Approach and was informed by TPB.</p> <p>Results</p> <p>Healthy eating was often viewed as being of greater importance for the health of mother and baby than participation in physical activity. A commonly cited motivator for maintaining physical activity during pregnancy is an aid to reducing pregnancy-related weight gain. However, participants often described how they would wait until the postnatal period to try and lose weight. A wide range of barriers to physical activity during pregnancy were highlighted including both internal (physical and psychological) and external (work, family, time and environmental). The study participants also lacked access to consistent information, advice and support on the benefits of physical activity during pregnancy.</p> <p>Conclusions</p> <p>Interventions to encourage recommended levels of physical activity in pregnancy should be accompanied by accessible and consistent information about the positive effects for mother and baby. More research is required to examine how to overcome barriers to physical activity and to understand which interventions could be most effective for overweight/obese pregnant women. Midwives should be encouraged to do more to promote activity in pregnancy.</p

How does the built environment affect teenagers (aged 13–14) physical activity and fitness? A cross-sectional analysis of the ACTIVE Project

Built environments have been cited as important facilitators of activity and research using geographic information systems (GIS) has emerged as a novel approach in exploring environmental determinants. The Active Children Through Individual Vouchers Evaluation Project used GIS to conduct a cross-sectional analysis of how teenager's (aged 13-14) environments impacted on their amount of activity and influences fitness. The ACTIVE Project recruited 270 participants aged 13-14 (year 9) from 7 secondary schools in south Wales, UK. Demographic data and objective measures of accelerometery and fitness were collected from each participant between September and December 2016. Objective data was mapped in a GIS alongside datasets relating to activity provision, active travel routes, public transport stops, main roads and natural resources. This study shows that fitness and physical activity are not correlated. Teenagers who had higher levels of activity also had higher levels of sedentary time/inactivity. Teenagers showed higher amounts of moderate-to-vigorous physical activity if their homes were closer to public transport. However, they were also more active if their schools were further away from public transport and natural resources. Teenagers were fitter if schools were closer to natural resources. Sedentary behaviour, fitness and activity do not cluster in the same teenagers. Policymakers/planning committees need to consider this when designing teenage friendly environments. Access to public transport, active travel, green space and activities that teenagers want, and need could make a significant difference to teenage health

Resource Quantity Affects Benthic Microbial Community Structure and Growth Efficiency in a Temperate Intertidal Mudflat

Estuaries cover <1% of marine habitats, but the carbon dioxide (CO2) effluxes from these net heterotrophic systems contribute significantly to the global carbon cycle. Anthropogenic eutrophication of estuarine waterways increases the supply of labile substrates to the underlying sediments. How such changes affect the form and functioning of the resident microbial communities remains unclear. We employed a carbon-13 pulse-chase experiment to investigate how a temperate estuarine benthic microbial community at 6.5°C responded to additions of marine diatom-derived organic carbon equivalent to 4.16, 41.60 and 416.00 mmol C m−2. The quantities of carbon mineralized and incorporated into bacterial biomass both increased significantly, albeit differentially, with resource supply. This resulted in bacterial growth efficiency increasing from 0.40±0.02 to 0.55±0.04 as substrates became more available. The proportions of diatom-derived carbon incorporated into individual microbial membrane fatty acids also varied with resource supply. Future increases in labile organic substrate supply have the potential to increase both the proportion of organic carbon being retained within the benthic compartment of estuaries and also the absolute quantity of CO2 outgassing from these environments

The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model

Friedreich ataxia (FRDA) is caused by homozygosity for FXN alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence. This expanded GAA-TR sequence is unstable in somatic cells of FRDA patients, showing age-dependent expansions in dorsal root ganglia (DRG), the tissue where pathology occurs earliest and is most significant. This is thought to be the basis for the progressive, tissue-specific pathology seen in FRDA, but the mechanism(s) for this somatic instability is unknown. We show that transgenic mice containing the expanded GAA-TR sequence (190 or 82 triplets) in the context of the human FXN locus show tissue-specific and age-dependent somatic instability that mimics the human condition. Small pool PCR analysis, which allows quantitative analysis of instability by assaying individual transgenes in vivo, showed age-dependent expansions specifically in the cerebellum and DRG. The (GAA)190 allele showed some instability by 2 months, progressed at about 0.3 – 0.4 triplets/week, resulting in a significant number of expansions by 12 months. Repeat length determined the age of onset of somatic instability, and the rate and magnitude of expansion. Whereas the GAA-TR was unstable in the context of the human FXN locus, pure GAATR sequences at other genetic loci in the human and murine genomes showed no instability. These data indicate that somatic instability of the GAA-TR sequence in the human FXN gene is determined by a combination of unique cis and trans-acting factors. This mouse model will serve as a useful tool to delineate the mechanism(s) of diseasespecific somatic instability in FRDA

Comparative Linkage Meta-Analysis Reveals Regionally-Distinct, Disparate Genetic Architectures: Application to Bipolar Disorder and Schizophrenia

New high-throughput, population-based methods and next-generation sequencing capabilities hold great promise in the quest for common and rare variant discovery and in the search for ”missing heritability.” However, the optimal analytic strategies for approaching such data are still actively debated, representing the latest rate-limiting step in genetic progress. Since it is likely a majority of common variants of modest effect have been identified through the application of tagSNP-based microarray platforms (i.e., GWAS), alternative approaches robust to detection of low-frequency (1–5% MAF) and rare (<1%) variants are of great importance. Of direct relevance, we have available an accumulated wealth of linkage data collected through traditional genetic methods over several decades, the full value of which has not been exhausted. To that end, we compare results from two different linkage meta-analysis methods—GSMA and MSP—applied to the same set of 13 bipolar disorder and 16 schizophrenia GWLS datasets. Interestingly, we find that the two methods implicate distinct, largely non-overlapping, genomic regions. Furthermore, based on the statistical methods themselves and our contextualization of these results within the larger genetic literatures, our findings suggest, for each disorder, distinct genetic architectures may reside within disparate genomic regions. Thus, comparative linkage meta-analysis (CLMA) may be used to optimize low-frequency and rare variant discovery in the modern genomic era