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Journal articleSuzuki HS, Gao HG, Bai WB, et al., 2017,
Abnormal brain white matter microstructure is associated withboth pre-hypertension and hypertension
, PLoS ONE, Vol: 12, ISSN: 1932-6203ObjectivesTo characterize effects of chronically elevated blood pressure on the brain, we tested for brain white matter microstructural differences associated with normotension, pre-hypertension and hypertension in recently available brain magnetic resonance imaging data from 4659 participants without known neurological or psychiatric disease (62.3±7.4 yrs, 47.0% male) in UK Biobank.MethodsFor assessment of white matter microstructure, we used measures derived from neurite orientation dispersion and density imaging (NODDI) including the intracellular volume fraction (an estimate of neurite density) and isotropic volume fraction (an index of the relative extra-cellular water diffusion). To estimate differences associated specifically with blood pressure, we applied propensity score matching based on age, sex, educational level, body mass index, and history of smoking, diabetes mellitus and cardiovascular disease to perform separate contrasts of non-hypertensive (normotensive or pre-hypertensive, N = 2332) and hypertensive (N = 2337) individuals and of normotensive (N = 741) and pre-hypertensive (N = 1581) individuals (p<0.05 after Bonferroni correction).ResultsThe brain white matter intracellular volume fraction was significantly lower, and isotropic volume fraction was higher in hypertensive relative to non-hypertensive individuals (N = 1559, each). The white matter isotropic volume fraction also was higher in pre-hypertensive than in normotensive individuals (N = 694, each) in the right superior longitudinal fasciculus and the right superior thalamic radiation, where the lower intracellular volume fraction was observed in the hypertensives relative to the non-hypertensive group.SignificancePathological processes associated with chronically elevated blood pressure are associated with imaging differences suggesting chronic alterations of white matter axonal structure that may affect cognitive functions even with pre-hypertension.
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Journal articleToledano MB, Mueller W, Fleming C, et al., 2017,
Total recall in the SCAMP Cohort: Validation of self-reported mobile phone use in the smartphone era
, Environmental Research, Vol: 161, Pages: 1-8, ISSN: 0013-9351Mobile phone use, predominantly smartphones, is almost ubiquitous amongst both adults and children. However adults and children have different usage patterns. A major challenge with research on mobile phone use is the reliability of self-reported phone activity for accurate exposure assessment. We investigated the agreement between self-reported mobile phone use data and objective mobile operator traffic data in a subset of adolescents aged 11-12 years participating in the Study of Cognition, Adolescents and Mobile Phones (SCAMP) cohort. We examined self-reported mobile phone use, including call frequency, cumulative call time duration and text messages sent among adolescents from SCAMP and matched these data with records provided by mobile network operators (n = 350). The extent of agreement between self-reported mobile phone use and mobile operator traffic data use was evaluated using Cohen's weighted Kappa (ĸ) statistics. Sensitivity and specificity of self-reported low (< 1 call/day, ≤ 5min of call/day or ≤ 5 text messages sent/day) and high (≥ 11 calls/day, > 30min of call/day or ≥ 11 text messages sent /day) use were estimated. Agreement between self-reported mobile phone use and mobile operator traffic data was highest for the duration spent talking on mobile phones per day on weekdays (38.9%) and weekends (29.4%) compared to frequency of calls and number of text messages sent. Adolescents overestimated their mobile phone use during weekends compared to weekdays. Analysis of agreement showed little difference overall between the sexes and socio-economic groups. Weighted kappa between self-reported and mobile operator traffic data for call frequency during weekdays was κ = 0.12, 95% CI 0.06-0.18. Of the three modes of mobile phone use measured in the questionnaire, call frequency was the most sensitive for low mobile phone users on weekdays and weekends (77.1, 95% CI: 69.3-83.7 and 72.0, 95% CI: 65.0-78.4, respectively). Specificity was
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Journal articleKraja AT, Evangelou E, Tzoulaki I, et al., 2017,
New blood pressure associated loci identified in meta-analyses of 475,000 individuals
, Circulation: Cardiovascular Genetics, Vol: 10, ISSN: 1942-325XBackground—Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Methods and Results—Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10−8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.Conclusions—We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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Journal articleWarren HR, Evangelou E, Cabrera CP, et al., 2017,
Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk (vol 49, pg 403, 2017)
, NATURE GENETICS, Vol: 49, Pages: 1558-1558, ISSN: 1061-4036- Author Web Link
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Journal articleToledano MB, Auvinen A, Tettamanti G, et al., 2017,
An international prospective cohort study of mobile phone users and health (COSMOS): Factors affecting validity of self-reported mobile phone use.
, International Journal of Hygiene and Environmental Health, Vol: 221, Pages: 1-8, ISSN: 1438-4639This study investigates validity of self-reported mobile phone use in a subset of 75 993 adults from the COSMOS cohort study. Agreement between self-reported and operator-derived mobile call frequency and duration for a 3-month period was assessed using Cohen's weighted Kappa (κ). Sensitivity and specificity of both self-reported high (≥10 calls/day or ≥4h/week) and low (≤6 calls/week or <30min/week) mobile phone use were calculated, as compared to operator data. For users of one mobile phone, agreement was fair for call frequency (κ=0.35, 95% CI: 0.35, 0.36) and moderate for call duration (κ=0.50, 95% CI: 0.49, 0.50). Self-reported low call frequency and duration demonstrated high sensitivity (87% and 76% respectively), but for high call frequency and duration sensitivity was lower (38% and 56% respectively), reflecting a tendency for greater underestimation than overestimation. Validity of self-reported mobile phone use was lower in women, younger age groups and those reporting symptoms during/shortly after using a mobile phone. This study highlights the ongoing value of using self-report data to measure mobile phone use. Furthermore, compared to continuous scale estimates used by previous studies, categorical response options used in COSMOS appear to improve validity considerably, most likely by preventing unrealistically high estimates from being reported.
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Journal articleCarding SR, Davis N, Hoyles L, 2017,
Review article: The human intestinal virome in health and disease
, Alimentary Pharmacology and Therapeutics, Vol: 46, Pages: 800-815, ISSN: 1365-2036Background: The human virome consists of animal-cell viruses causing transient infections, bacteriophage (phage) predators of bacteria and archaea, endogenous retroviruses, and viruses causing persistent and latent infections. High-throughput, inexpensive, sensitive sequencing methods and metagenomics have made it possible to study the contribution dsDNA, ssDNA and RNA virus-like particles make to the human virome, and in particular the intestinal virome. Aim: To review and evaluate the pioneering studies that have attempted to characterise the human virome and generated an increased interest in understanding how the intestinal virome might contribute to maintaining health, and the pathogenesis of chronic diseases. Methods: Relevant virome-related articles were selected for review following extensive language- and date-unrestricted, electronic searches of the literature.Results: The human intestinal virome is personalized and stable, and dominated by phages. It develops soon after birth in parallel with prokaryotic communities of the microbiota, becoming established during the first few years of life. By infecting specific populations of bacteria, phages can alter microbiota structure by killing host cells or altering their phenotype, enabling phages to contribute to maintaining intestinal homeostasis or to dysbiosis and the development of chronic infectious and autoimmune diseases including HIV infection and Crohn’s disease, respectively. Conclusions: Our understanding of the intestinal virome is fragmented and requires standardized methods for virus isolation and sequencing to provide a more complete picture of the virome, which is key to explaining the basis of virome–disease associations, and how enteric viruses can contribute to disease aetiologies and be rationalized as targets for interventions in disease states.
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Journal articlecastagne R, Boulange CL, Karaman I, et al., 2017,
Improving visualisation and interpretation of metabolome-wide association studies (MWAS): an application in a population-based cohort using untargeted 1H NMR metabolic profiling.
, Journal of Proteome Research, Vol: 16, Pages: 3623-3633, ISSN: 1535-38931H NMR spectroscopy of biofluids generates reproducible data allowing detection and quantification of small molecules in large population cohorts. Statistical models to analyze such data are now well-established, and the use of univariate metabolome wide association studies (MWAS) investigating the spectral features separately has emerged as a computationally efficient and interpretable alternative to multivariate models. The MWAS rely on the accurate estimation of a metabolome wide significance level (MWSL) to be applied to control the family wise error rate. Subsequent interpretation requires efficient visualization and formal feature annotation, which, in-turn, call for efficient prioritization of spectral variables of interest. Using human serum 1H NMR spectroscopic profiles from 3948 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), we have performed a series of MWAS for serum levels of glucose. We first propose an extension of the conventional MWSL that yields stable estimates of the MWSL across the different model parameterizations and distributional features of the outcome. We propose both efficient visualization methods and a strategy based on subsampling and internal validation to prioritize the associations. Our work proposes and illustrates practical and scalable solutions to facilitate the implementation of the MWAS approach and improve interpretation in large cohort studies.
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Journal articleMousas A, Ntritsos G, Chen M-H, et al., 2017,
Rare coding variants pinpoint genes that control human hematological traits.
, Plos Genetics, Vol: 13, ISSN: 1553-7404The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45–0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39–0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
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Journal articleDouglas P, Freni-Sterrantino A, Leal Sanchez M, et al., 2017,
Estimating Particulate Exposure from Modern Municipal Waste Incinerators in Great Britain
, Environmental science & technology, Vol: 51, Pages: 7511-7519, ISSN: 0013-936XMunicipal Waste Incineration (MWI) is regulated through the European Union Directive on Industrial Emissions (IED), but there is ongoing public concern regarding potential hazards to health. Using dispersion modeling, we estimated spatial variability in PM10 concentrations arising from MWIs at postcodes (average 12 households) within 10 km of MWIs in Great Britain (GB) in 2003-2010. We also investigated change points in PM10 emissions in relation to introduction of EU Waste Incineration Directive (EU-WID) (subsequently transposed into IED) and correlations of PM10 with SO2, NOx, heavy metals, polychlorinated dibenzo-p-dioxins/furan (PCDD/F), polycyclic aromatic hydrocarbon (PAH) and polychlorinated biphenyl (PCB) emissions. Yearly average modeled PM10 concentrations were 1.00 × 10-5 to 5.53 × 10-2 μg m-3, a small contribution to ambient background levels which were typically 6.59-2.68 × 101 μg m-3, 3-5 orders of magnitude higher. While low, concentration surfaces are likely to represent a spatial proxy of other relevant pollutants. There were statistically significant correlations between PM10 and heavy metal compounds (other heavy metals (r = 0.43, p = <0.001)), PAHs (r = 0.20, p = 0.050), and PCBs (r = 0.19, p = 0.022). No clear change points were detected following EU-WID implementation, possibly as incinerators were operating to EU-WID standards before the implementation date. Results will be used in an epidemiological analysis examining potential associations between MWIs and health outcomes.
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Journal articleDumas M, Rothwell AR, Hoyles L, et al., 2017,
Microbial-host co-metabolites are prodromal markers predicting phenotypic heterogeneity in behavior, obesity and impaired glucose tolerance
, Cell Reports, Vol: 20, Pages: 136-148, ISSN: 2211-1247The influence of the gut microbiome on metabolic and behavioral traits is now widely accepted, though the microbiome-derived metabolites involved remain unclear. We carried out untargeted urine 1H NMR spectroscopy-based metabolic phenotyping in an isogenic C57BL/6J mouse population (n=50) and show that microbial-host co-metabolites are prodromal (i.e., early) markers predicting future divergence in metabolic (obesity and glucose homeostasis) and behaviorial (anxiety and activity) outcomes with 94-100% accuracy. Some of these metabolites also modulate disease phenotypes, best illustrated by trimethylamine-N-oxide (TMAO), a product of microbial-host co-metabolism predicting future obesity, impaired glucose tolerance (IGT) and behavior, whilst reducing endoplasmic reticulum stress and lipogenesis in 3T3-L1 adipocytes. Chronic in vivo TMAO treatment limits IGT in HFD-fed mice and isolated pancreatic islets by increasing insulin secretion. We highlight the prodromal potential of microbial metabolites to predict disease outcomes and their potential in shaping mammalian phenotypic heterogeneity.
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