Biology subjects

Davies, N.

Publications and source records attributed to Davies, N..

5 recordsLinked to original sources

bioRxiv2018

Common genetic variants and health outcomes appear geographically structured in the UK Biobank sample: Old concerns returning and their implications.

Introductory paragraphThe inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis.\n\nWe found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.

genetics↗

bioRxiv2017

The molecular genetics of participation in the Avon Longitudinal Study of Parents and Children

BackgroundIt is often assumed that selection (including participation and dropout) does not represent an important source of bias in genetic studies. However, there is little evidence to date on the effect of genetic factors on participation.\n\nMethodsUsing data on mothers (N=7,486) and children (N=7,508) from the Avon Longitudinal Study of Parents and Children, we 1) examined the association of polygenic risk scores for a range of socio-demographic, lifestyle characteristics and health conditions related to continued participation, 2) investigated whether associations of polygenic scores with body mass index (BMI; derived from self-reported weight and height) and self-reported smoking differed in the largest sample with genetic data and a sub-sample who participated in a recent follow-up and 3) determined the proportion of variation in participation explained by common genetic variants using genome-wide data.\n\nResultsWe found evidence that polygenic scores for higher education, agreeableness and openness were associated with higher participation and polygenic scores for smoking initiation, higher BMI, neuroticism, schizophrenia, ADHD and depression were associated with lower participation. Associations between the polygenic score for education and self-reported smoking differed between the largest sample with genetic data (OR for ever smoking per SD increase in polygenic score:0.85, 95% CI:0.81,0.89) and sub-sample (OR:0.95, 95% CI:0.88,1.02). In genome-wide analysis, single nucleotide polymorphism based heritability explained 17-31% of variability in participation.\n\nConclusionsGenetic association studies, including Mendelian randomization, can be biased by selection, including loss to follow-up. Genetic risk for dropout should be considered in all analyses of studies with selective participation.

genetics↗

bioRxiv2017

Impaired brain glymphatic flow in a rodent model of chronic liver disease and minimal hepatic encephalopathy

Neuronal function is exquisitely sensitive to alterations in extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain may contribute to neuronal dysfunction and cognitive impairment. In a rat model of chronic liver disease, we used an emerging dynamic contrast-enhanced MRI technique to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic flow, which aligned with cognitive/behavioural deficits. Although the underlying pathophysiological mechanisms remain unclear, this study provides the first experimental evidence of impaired glymphatic clearance in HE.

pathology↗

bioRxiv2017

MCE domain proteins: conserved inner membrane lipid-binding proteins required for outer membrane homeostasis

Bacterial proteins with MCE domains were first described as being important for Mammalian Cell Entry. More recent evidence suggests they are components of lipid ABC transporters. In Escherichia coli, the single-domain protein MlaD is known to be part of an inner membrane transporter that is important for maintenance of outer membrane lipid asymmetry. Here we describe two multi MCE domain-containing proteins in Escherichia coli, PqiB and YebT, the latter of which is an orthologue of MAM-7 that was previously reported to be an outer membrane protein. We show that all three MCE domain-containing proteins localise to the inner membrane. Bioinformatic analyses revealed that MCE domains are widely distributed across bacterial phyla but multi MCE domain-containing proteins evolved in Proteobacteria from single-domain proteins. Mutants defective in mlaD, pqiAB and yebST were shown to have distinct but partially overlapping phenotypes, but the primary functions of PqiB and YebT differ from MlaD. Complementing our previous findings that all three proteins bind phospholipids, results presented here indicate that multi-domain proteins evolved in Proteobacteria for specific functions in maintaining cell envelope homeostasis.

microbiology↗

bioRxiv2017

Do early life non-cognitive skills matter?A systematic review and meta-analysis of early life effects on academic achievement, psychosocial, language and cognitive, and health outcomes

BackgroundSuccess in school and the labour market is due to more than just high intelligence. Associations between traits such as attention, self-regulation, and perseverance in childhood, and later outcomes have been investigated by psychologists, economists, and epidemiologists. Such traits have been loosely referred to as \"non-cognitive\" skills. There has been no attempt to systematically assess the relative importance of non-cognitive skills in early life on later outcomes.\n\nMethodsThe systematic review protocol was registered with the International Prospective Register for Systematic Reviews (PROSPERO, CRD42013006566) in December 2013. We systematically reviewed electronic databases covering psychology, education, health and economics for articles published from database conception until September 2015. Titles and abstracts were screened for eligibility, and from eligible articles data was extracted on study design, sample type and size, age of participants at exposure and outcome, loss to follow up, measurement of exposure and outcome, type of intervention and comparison group, confounding adjustment and results. Where possible we extracted a standardised effect size. We reviewed all studies and rated their evidence quality as better, weak, or poor on the basis of study design and potential for confounding, selection and measurement bias.\n\nResultsWe reviewed 375 studies and provided interpretation of results from 142 (38%) better quality studies comprising randomised controlled trials, quasi-experimental, fixed effects including twin studies, longitudinal and some cross-sectional designs that made reasonable attempts to control confounding. In the academic achievement category outcomes were reported in 78 publications of better quality studies which were consistent with 0.1-0.2 SD effects.\n\nPsychosocial outcomes were reported in 65 better quality studies consistent with effects of 0.3-0.4 SD. For the language and cognitive category there were 42 publications reporting better quality studies consistent with effects of 0.3-0.4 SD. For physical health, results across only eight better quality studies were inconsistent but centred around zero. Analysis of funnel plots consistently showed asymmetric distributions, raising the potential of small study bias which may inflate these observed effects.\n\nConclusionsThe evidence under-pinning the importance of non-cognitive skills for life success is diverse and inconsistent. Nevertheless, there is tentative evidence from published studies that non-cognitive skills associate with modest improvements in academic achievement, psychosocial, and language and cognitive outcomes with effects in the range of 0.2-0.4 SD. The quality of evidence under-pinning this field is generally low with more than a third of studies making little or no attempt to control even the most basic confounding (endogeneity) bias. The evidence could be improved by adequately powering studies, and using procedures and tools that improve the conduct and reporting of RCTs and observational studies. Interventions designed to develop childrens non-cognitive skills could potentially improve opportunities, particularly for disadvantaged children. The inter-disciplinary researchers interested in these skills should take a more rigorous approach to determine which interventions are most effective.

epidemiology↗