Journal articles
Price CJ, Pitfield J, Baker EAD, Hepplestone SP (2023). First principles study of layered scandium disulfide for use as Li-ion and beyond-Li-ion batteries.
Physical Chemistry Chemical Physics,
25(3), 2167-2178.
Abstract:
First principles study of layered scandium disulfide for use as Li-ion and beyond-Li-ion batteries.
This article shows the highly suitable potential of ScS2 as a cathode material, with suggested capacities comparable to NMC and other presently practiced electrode materials.
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DOI.
Evans BD, Słowiński P, Hattersley AT, Jones SE, Sharp S, Kimmitt RA, Weedon MN, Oram RA, Tsaneva-Atanasova K, Thomas NJ, et al (2021). Estimating disease prevalence in large datasets using genetic risk scores.
Nature Communications,
12(1)
Abstract:
Estimating disease prevalence in large datasets using genetic risk scores.
Clinical classification is essential for estimating disease prevalence but is difficult, often requiring complex investigations. The widespread availability of population level genetic data makes novel genetic stratification techniques a highly attractive alternative. We propose a generalizable mathematical framework for determining disease prevalence within a cohort using genetic risk scores. We compare and evaluate methods based on the means of genetic risk scores’ distributions; the Earth Mover’s Distance between distributions; a linear combination of kernel density estimates of distributions; and an Excess method. We demonstrate the performance of genetic stratification to produce robust prevalence estimates. Specifically, we show that robust estimates of prevalence are still possible even with rarer diseases, smaller cohort sizes and less discriminative genetic risk scores, highlighting the general utility of these approaches. Genetic stratification techniques offer exciting new research tools, enabling unbiased insights into disease prevalence and clinical characteristics unhampered by clinical classification criteria.
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DOI.
Ruth K, Beaumont RN, Frayling TM, Joaquim MDR, Shekari S, Tyrrell J, Wood AR, Murray A (2021). Genetic insights into biological mechanisms governing human ovarian ageing.
Nature Abstract:
Genetic insights into biological mechanisms governing human ovarian ageing.
Reproductive longevity is critical for fertility and impacts healthy ageing in women1,2, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ~200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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Foo M, Bates DG, Akman OE (2020). A simplified modelling framework facilitates more complex representations of plant circadian clocks.
PLoS Comput Biol,
16(3)
Abstract:
A simplified modelling framework facilitates more complex representations of plant circadian clocks.
The circadian clock orchestrates biological processes so that they occur at specific times of the day, thereby facilitating adaptation to diurnal and seasonal environmental changes. In plants, mathematical modelling has been comprehensively integrated with experimental studies to gain a better mechanistic understanding of the complex genetic regulatory network comprising the clock. However, with an increasing number of circadian genes being discovered, there is a pressing need for methods facilitating the expansion of computational models to incorporate these newly-discovered components. Conventionally, plant clock models have comprised differential equation systems based on Michaelis-Menten kinetics. However, the difficulties associated with modifying interactions using this approach-and the concomitant problem of robustly identifying regulation types-has contributed to a complexity bottleneck, with quantitative fits to experimental data rapidly becoming computationally intractable for models possessing more than ≈50 parameters. Here, we address these issues by constructing the first plant clock models based on the S-System formalism originally developed by Savageau for analysing biochemical networks. We show that despite its relative simplicity, this approach yields clock models with comparable accuracy to the conventional Michaelis-Menten formalism. The S-System formulation also confers several key advantages in terms of model construction and expansion. In particular, it simplifies the inclusion of new interactions, whilst also facilitating the modification of regulation types, thereby making it well-suited to network inference. Furthermore, S-System models mitigate the issue of parameter identifiability. Finally, by applying linear systems theory to the models considered, we provide some justification for the increased use of aggregated protein equations in recent plant clock modelling, replacing the separate cytoplasmic/nuclear protein compartments that were characteristic of the earlier models. We conclude that as well as providing a simplified framework for model development, the S-System formalism also possesses significant potential as a robust modelling method for designing synthetic gene circuits.
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Kraus S, Kreplin A, Young AK, Bate MR, Monnier JD, Harries TJ, Avenhaus H, Kluska J, Laws ASE, Rich EA, et al (2020). A triple star system with a misaligned and warped circumstellar disk. shaped by disk tearing.
Abstract:
A triple star system with a misaligned and warped circumstellar disk. shaped by disk tearing.
Young stars are surrounded by a circumstellar disk of gas and dust, within
which planet formation can occur. Gravitational forces in multiple star systems
can disrupt the disk. Theoretical models predict that if the disk is misaligned
with the orbital plane of the stars, the disk should warp and break into
precessing rings, a phenomenon known as disk tearing. We present observations
of the triple star system GWOrionis, finding evidence for disk tearing. Our
images show an eccentric ring that is misaligned with the orbital planes and
the outer disk. The ring casts shadows on a strongly warped intermediate region
of the disk. If planets can form within the warped disk, disk tearing could
provide a mechanism for forming wide-separation planets on oblique orbits.
Abstract.
Author URL.
Cunliffe AM, McIntire CD, Boschetti F, Sauer KJ, Litvak M, Anderson K, Brazier RE (2020). Allometric Relationships for Predicting Aboveground Biomass and Sapwood Area of Oneseed Juniper (Juniperus monosperma) Trees.
Frontiers in Plant Science,
11 Abstract:
Allometric Relationships for Predicting Aboveground Biomass and Sapwood Area of Oneseed Juniper (Juniperus monosperma) Trees.
Across the semi-arid ecosystems of the southwestern USA, there has been widespread encroachment of woody shrubs and trees including Juniperus species into former grasslands. Quantifying vegetation biomass in such ecosystems is important because semi-arid ecosystems are thought to play an important role in the global land carbon (C) sink, and changes in plant biomass also have implications for primary consumers and potential bioenergy feedstock. Oneseed Juniper (J. monosperma) is common in desert grasslands and pinyon-juniper rangelands across the intermountain region of southwestern North America; however, there is limited information about the aboveground biomass (AGB) and sapwood area (SWA) for this species, causing uncertainties in estimates of C stock and transpiration fluxes. In this study, we report on canopy area, stem diameter, maximum height and biomass measurements from J. monosperma trees sampled from central New Mexico. Dry biomass ranged between 0.4 kg and 625 kg, and cross-sectional sapwood area was measured on n=200 stems using image analysis. We found a strong linear relationship between canopy area and AGB (r2 = 0.96), with a similar slope to that observed in other juniper species, suggesting that this readily measured attribute is well suited for upscaling studies. There was a 9% bias between different approaches to measuring canopy area, indicating care should be taken to account for these differences to avoid systematic biases. We found equivalent stem diameter (ESD) was a strong predictor of biomass, but that existing allometric models under-predicted biomass in larger trees. We found sapwood area could be predicted from individual stem diameter with a power relationship, and that tree-level SWA should be estimated by summing the SWA predictions from individual stems rather than ESD. Our improved allometric models for J. monosperma support more accurate and robust measurements of C storage and transpiration fluxes in Juniperus-dominated ecosystems.
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De Franco E, Caswell R, Johnson MB, Wakeling MN, Zung A, Dũng VC, Bích Ngọc CT, Goonetilleke R, Vivanco Jury M, El-Khateeb M, et al (2020). De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.
Diabetes,
69(3), 477-483.
Abstract:
De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.
Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1's fundamental role within this pathway.
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Pilling LC, Jones LC, Masoli JAH, Delgado J, Atkins JL, Bowden J, Fortinsky RH, Kuchel GA, Melzer D (2020). Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older <scp>UK</scp> Biobank Participants.
Journal of the American Geriatrics Society,
69(2), 365-372.
Abstract:
Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older <scp>UK</scp> Biobank Participants.
BACKGROUND/OBJECTIVESDelirium is common in older adults, especially following hospitalization. Because low vitamin D levels may be associated with increased delirium risk, we aimed to determine the prognostic value of blood vitamin D levels, extending our previous genetic analyses of this relationship.DESIGNProspective cohort analysis.SETTINGCommunity‐based cohort study of adults from 22 cities across the United Kingdom (the UK Biobank).PARTICIPANTSAdults aged 60 and older by the end of follow‐up in the linked hospital inpatient admissions data, up to 14 years after baseline (n = 351,320).MEASUREMENTSAt baseline, serum vitamin D (25‐OH‐D) levels were measured. We used time‐to‐event models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D deficiency and incident hospital‐diagnosed delirium, adjusted for age, sex, assessment month, assessment center, and ethnicity. We performed Mendelian randomization genetic analysis in European participants to further investigate vitamin D and delirium risk.RESULTSA total of 3,634 (1.03%) participants had at least one incident hospital‐diagnosed delirium episode. Vitamin D deficiency (<25 nmol/L) predicted a large incidence in delirium (HR = 2.49; 95% CI = 2.24–2.76; P = 3*10−68, compared with >50 nmol/L). Increased risk was not limited to the deficient group: insufficient levels (25–50 nmol/L) were also at increased risk (HR = 1.38; 95% CI = 1.28–1.49; P = 4*10−18). The association was independent of calcium levels, hospital‐diagnosed fractures, dementia, and other relevant cofactors. In genetic analysis, participants carrying more vitamin D–increasing variants had a reduced likelihood of incident delirium diagnosis (HR =. 80 per standard deviation increase in genetically instrumented vitamin D:. 73–.87; P = 2*10−7).CONCLUSIONProgressively lower vitamin D levels predicted increased risks of incident hospital‐diagnosed delirium, and genetic evidence supports a shared causal pathway. Because low vitamin D levels are simple to detect and inexpensive and safe to correct, an intervention trial to confirm these results is urgently needed.
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Ireland LG, Zanni C, Matt SP, Pantolmos G (2020). Magnetic Braking of Accreting T Tauri Stars: Effects of Mass Accretion Rate, Rotation, and Dipolar Field Strength.
Astrophysical Journal,
906(1)
Abstract:
Magnetic Braking of Accreting T Tauri Stars: Effects of Mass Accretion Rate, Rotation, and Dipolar Field Strength.
The rotational evolution of an accreting pre-main-sequence star is influenced by its magnetic interaction with its surrounding circumstellar disk. Using the PLUTO code, we perform 2.5D magnetohydrodynamic, axisymmetric, time-dependent simulations of star-disk interaction - with an initial dipolar magnetic field structure, and a viscous and resistive accretion disk - in order to model the three mechanisms that contribute to the net stellar torque: accretion flow, stellar wind, and magnetospheric ejections (periodic inflation and reconnection events). We investigate how changes in the stellar magnetic field strength, rotation rate, and mass accretion rate (changing the initial disk density) affect the net stellar torque. All simulations are in a net spin-up regime. We fit semi-analytic functions for the three stellar torque contributions, allowing for the prediction of the net stellar torque for our parameter regime, as well as the possibility of investigating spin evolution using 1D stellar evolution codes. The presence of an accretion disk appears to increase the efficiency of stellar torques compared to isolated stars, for cases with outflow rates much smaller than accretion rates, because the star-disk interaction opens more of the stellar magnetic flux compared to that from isolated stars. In our parameter regime, a stellar wind with a mass-loss rate of ≈1% of the mass accretion rate is capable of extracting ≲50% of the accreting angular momentum. These simulations suggest that achieving spin equilibrium in a representative T Tauri case within our parameter regime, e.g. BP Tau, would require a wind mass-loss rate of ≈25% of the mass accretion rate.
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Bending TJR, Dobbs CL, Bate MR (2020). Photoionising feedback in spiral arm molecular clouds.
Abstract:
Photoionising feedback in spiral arm molecular clouds.
We present simulations of a 500 pc$^2$ region, containing gas of mass 4
$\times$ 10$^6$ M$_\odot$, extracted from an entire spiral galaxy simulation,
scaled up in resolution, including photoionising feedback from stars of mass >
18 M$_\odot$. Our region is evolved for 10 Myr and shows clustered star
formation along the arm generating $\approx$ 5000 cluster sink particles
$\approx$ 5% of which contain at least one of the $\approx$ 4000 stars of mass
> 18 M$_\odot$. Photoionisation has a noticeable effect on the gas in the
region, producing ionised cavities and leading to dense features at the edge of
the HII regions. Compared to the no-feedback case, photoionisation produces a
larger total mass of clouds and clumps, with around twice as many such objects,
which are individually smaller and more broken up. After this we see a rapid
decrease in the total mass in clouds and the number of clouds. Unlike studies
of isolated clouds, our simulations follow the long range effects of
ionisation, with some already-dense gas becoming compressed from multiple sides
by neighbouring HII regions. This causes star formation that is both
accelerated and partially displaced throughout the spiral arm with up to 30% of
our cluster sink particle mass forming at distances > 5 pc from sites of sink
formation in the absence of feedback. At later times, the star formation rate
decreases to below that of the no-feedback case.
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Avramidis E, Lalik M, Akman OE (2020). SODECL.
ACM Transactions on Mathematical Software,
46(3), 1-21.
Abstract:
SODECL.
Stochastic differential equations (SDEs) are widely used to model systems affected by random processes. In general, the analysis of an SDE model requires numerical solutions to be generated many times over multiple parameter combinations. However, this process often requires considerable computational resources to be practicable. Due to the embarrassingly parallel nature of the task, devices such as multi-core processors and graphics processing units (GPUs) can be employed for acceleration.
. Here, we present SODECL (https://github.com/avramidis/sodecl), a software library that utilizes such devices to calculate multiple orbits of an SDE model. To evaluate the acceleration provided by SODECL, we compared the time required to calculate multiple orbits of an exemplar stochastic model when one CPU core is used, to the time required when using all CPU cores or a GPU. In addition, to assess scalability, we investigated how model size affected execution time on different parallel compute devices.
. Our results show that when using all 32 CPU cores of a high-end high-performance computing node, the task is accelerated by a factor of up to ≈6.7, compared to when using a single CPU core. Executing the task on a high-end GPU yielded accelerations of up to ≈4.5, compared to a single CPU core.
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Jones G, Pilling LC, Kuo C-L, Kuchel G, Ferrucci L, Melzer D (2020). Sarcopenia and Variation in the Human Leukocyte Antigen Complex.
J Gerontol a Biol Sci Med Sci,
75(2), 301-308.
Abstract:
Sarcopenia and Variation in the Human Leukocyte Antigen Complex.
BACKGROUND: Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. METHODS: Data were collected from 181,301 UK Biobank European descent volunteers aged 60-70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. RESULTS: Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74-1.92, p = 4.0*10-125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p = 2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12-1.35, p = 7.28*10-6). of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05-1.11, p = 1.06*10-8 and 1.07, CI 1.04-1.09, p = 1.5*10-6, respectively). Some HLA associations with sarcopenia were greater in female participants. CONCLUSION: Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.
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Kuo C-L, Joaquim M, Kuchel GA, Ferrucci L, Harries LW, Pilling LC, Melzer D (2020). The Longevity-Associated SH2B3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects.
J Gerontol a Biol Sci Med Sci,
75(9), 1656-1662.
Abstract:
The Longevity-Associated SH2B3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects.
Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal, and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were obtained from 379,758 European-descent UK Biobank participants, aged 40-70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers aged ≥96 years) was more common in CC versus TT (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR = 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR = 1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target.
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Ruth KS, Day FR, Tyrrell J, Thompson DJ, Wood AR, Mahajan A, Beaumont RN, Wittemans L, Martin S, Busch AS, et al (2020). Using human genetics to understand the disease impacts of testosterone in men and women.
Nature Medicine,
26(2), 252-258.
DOI.
Casanova F, Tyrrell J, Beaumont RN, Ji Y, Jones SE, Hattersley AT, Weedon MN, Murray A, Shore AC, Frayling TM, et al (2019). A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.
Hum Mol Genet,
28(24), 4197-4207.
Abstract:
A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.
Raised albumin-creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular-related disease. We performed a genome-wide association study of ACR using 437 027 individuals from the UK Biobank in the discovery phase, 54 527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P 0.8) coinciding with signals for at least 16 related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes-a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene-diabetes interactions (P ≤ 4 × 10-5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR.
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Wright CF, West B, Tuke M, Jones SE, Patel K, Laver TW, Beaumont RN, Tyrrell J, Wood AR, Frayling TM, et al (2019). Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
American Journal of Human Genetics,
104(2), 275-286.
Abstract:
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as “clinically relevant” variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
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Bewshea CM, Ahmad T, Kennedy N, Weedon M, Harrison J, Walker G, Goodhand J, Jones S (2019). Association of Genetic Variants in NUDT15 with Thiopurine-Induced
Myelosuppression in Patients with Inflammatory Bowel Disease.
JAMA - Journal of the American Medical Association,
321 (8), 773-785.
DOI.
Thompson WD, Tyrrell J, Borges MC, Beaumont RN, Knight BA, Wood AR, Ring SM, Hattersley AT, Freathy RM, Lawlor DA, et al (2019). Association of maternal circulating 25(OH)D and calcium with birth weight: a mendelian randomisation analysis.
PLoS Medicine,
16 DOI.
Słowiński P, Sheybani L, Michel CM, Richardson MP, Quairiaux C, Terry JR, Goodfellow M (2019). Background EEG connectivity captures the time-course of epileptogenesis in a mouse model of epilepsy.
eneuro, ENEURO.0059-ENEU19.2019.
Abstract:
Background EEG connectivity captures the time-course of epileptogenesis in a mouse model of epilepsy.
Large-scale brain networks are increasingly recognized as important for the generation of seizures in epilepsy. However, how a network evolves from a healthy state through the process of epileptogenesis remains unclear. To address this question, here, we study longitudinal epicranial background EEG recordings (30 electrodes, EEG free from epileptiform activity) of a mouse model of mesial temporal lobe epilepsy. We analyse functional connectivity networks and observe that over the time-course of epileptogenesis the networks become increasingly asymmetric. Furthermore, computational modelling reveals that a set of nodes, located outside of the region of initial insult, emerges as particularly important for the network dynamics. These findings are consistent with experimental observations, thus demonstrating that ictogenic mechanisms can be revealed on the EEG, that computational models can be used to monitor unfolding epileptogenesis and that both the primary focus and epileptic network play a role in epileptogenesis.Significance Statement We provide the first description of how functional connectivity and network dynamics inferred from background EEG evolve during epileptogenesis. We focus on background EEG because it allows for direct comparison of functional networks before and after experimental intervention. We show that network dynamics inferred by means of computational modelling are different at early and later stages of epileptogenesis. Our findings provide further support for clinical potential of background EEG.
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Lane JM, Jones SE, Dashti HS, Wood AR, Aragam KG, van Hees VT, Strand LB, Winsvold BS, Wang H, Bowden J, et al (2019). Biological and clinical insights from genetics of insomnia symptoms.
Nature Genetics Abstract:
Biological and clinical insights from genetics of insomnia symptoms.
Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n = 14,923 cases, 47,610 controls), physician-diagnosed insomnia in Partners Biobank (n = 2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms and subjective well-being.
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Pilling L, Tamosauskaite J, Jones G, Wood A, Jones L, Kuo C-L, Kuchel G, Ferrucci L, Melzer D (2019). Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank.
BMJ DOI.
Dobbs CL, Rosolowsky E, Pettitt AR, Braine J, Corbelli E, Sun J (2019). Comparing the properties of GMCs in M33 from simulations and observations.
Monthly Notices of the Royal Astronomical Society,
485(4), 4997-5009.
Abstract:
Comparing the properties of GMCs in M33 from simulations and observations.
We compare the properties of clouds in simulated M33 galaxies to those observed in the real M33. We apply a friends of friends algorithm and CPROPS to identify clouds, as well as a pixel-by-pixel analysis. We obtain very good agreement between the number of clouds, and maximum mass of clouds. Both are lower than occurs for a Milky Way-type galaxy and thus are a function of the surface density, size, and galactic potential of M33. We reproduce the observed dependence of molecular cloud properties on radius in the simulations, and find this is due to the variation in gas surface density with radius. The cloud spectra also show good agreement between the simulations and observations, but the exact slope and shape of the spectra depend on the algorithm used to find clouds, and the range of cloud masses included when fitting the slope. Properties such as cloud angular momentum, velocity dispersions, and virial relation are also in good agreement between the simulations and observations, but do not necessarily distinguish between simulations of M33 and other galaxy simulations. Our results are not strongly dependent on the level of feedback used here (10 and 20 per cent) although they suggest that 15 per cent feedback efficiency may be optimal. Overall our results suggest that the molecular cloud properties are primarily dependent on the gas and mass surface density, and less dependent on the localized physics such as the details of stellar feedback, or the numerical code used.
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Wurster J, Bate MR (2019). Disc formation and fragmentation using radiative non-ideal magnetohydrodynamics.
Monthly Notices of the Royal Astronomical Society,
486(2), 2587-2603.
Abstract:
Disc formation and fragmentation using radiative non-ideal magnetohydrodynamics.
We investigate the formation and fragmentation of discs using a suite of 3D smoothed particle radiative magnetohydrodynamics simulations. Our models are initialized as 1 M- rotating Bonnor-Ebert spheres that are threaded with a uniform magnetic field. We examine the effect of including ideal and non-ideal magnetic fields, the orientation and strength of the magnetic field, and the initial rotational rate. We follow the gravitational collapse and early evolution of each system until the final classification of the protostellar disc can be determined. of our 105 models, 41 fragment, 21 form a spiral structure but do not fragment, and another 12 form smooth discs. Fragmentation is more likely to occur for faster initial rotation rates and weaker magnetic fields. For stronger magnetic field strengths, the inclusion of non-ideal MHD promotes disc formation, and several of these models fragment, whereas their ideal MHD counterparts do not. For the models that fragment, there is no correlation between our parameters and where or when the fragmentation occurs. Bipolar outflows are launched in only 17 models, and these models have strong magnetic fields that are initially parallel to the rotation axis. Counter-rotating envelopes form in four slowly rotating, strong-field models - including one ideal MHD model - indicating they form only in a small fraction of the parameter space investigated.
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Debras F, Mayne N, Baraffe I, Goffrey T, Thuburn J (2019). Eigenvectors, Circulation and Linear Instabilities for Planetary Science. in 3 Dimensions (ECLIPS3D).
A,
631 Abstract:
Eigenvectors, Circulation and Linear Instabilities for Planetary Science. in 3 Dimensions (ECLIPS3D).
Context. The study of linear waves and instabilities is necessary to
understand the physical evolution of an atmosphere, and can provide physical
interpretation of the complex flows found in simulations performed using Global
Circulation Models (GCM). In particular, the acceleration of superrotating flow
at the equator of hot Jupiters has mostly been studied under several
simplifying assumptions, the relaxing of which may impact final results. Aims.
We develop and benchmark a publicly available algorithm to identify the
eigenmodes of an atmosphere around any initial steady state. We also solve for
linear steady states. Methods. We linearise the hydrodynamical equations of a
planetary atmosphere in a steady state with arbitrary velocities and thermal
profile. We then discretise the linearised equations on an appropriate
staggered grid, and solve for eigenvectors and linear steady solutions with the
use of a parallel library for linear algebra: ScaLAPACK. We also implement a
posteriori calculation of an energy equation in order to obtain more
information on the underlying physics of the mode. Results. Our code is
benchmarked against classical wave and instability test cases in multiple
geometries. The steady linear circulation calculations also reproduce expected
results for the atmosphere of hot Jupiters. We finally show the robustness of
our energy equation, and its power to obtain physical insight into the modes.
Conclusions. We have developed and benchmarked a code for the study of linear
processes in planetary atmospheres, with an arbitrary steady state. The
calculation of an a posteriori energy equation provides both increased
robustness and physical meaning to the obtained eigenmodes. This code can be
applied to various problems, and notably to further study the initial spin up
of superrotation of GCM simulations of hot Jupiter.
Abstract.
Author URL.
Goyal J, Mayne N, Sing D, Drummond B, Tremblin PLR, Amundsen DS, Evans T, Carter A, Spake J, Baraffe I, et al (2019). Erratum: a library of ATMO forward model transmission spectra for hot Jupiter exoplanets.
MONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY,
486(1), 783-795.
DOI.
Budu-Aggrey A, Brumpton B, Tyrrell J, Watkins S, Modasli E, Celis-Morales C, Ferguson L, Vie G, Palmer T, Fritsche L, et al (2019). Evidence of a causal relationship between body mass index and psoriasis: a mendelian randomization study.
PLoS Medicine DOI.
Bovijn J, Jackson L, Censin J, Chen CY, Laisk T, Laber S, Ferreira T, Pulit SL, Glastonbury CA, Smoller JW, et al (2019). GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.
American Journal of Human Genetics,
104(1), 157-163.
Abstract:
GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.
Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10−14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.
Abstract.
DOI.
Alves AC, De Silva NMG, Karhunen V, Sovio U, Das S, Rob Taal H, Warrington NM, Lewin AM, Kaakinen M, Cousminer DL, et al (2019). GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.
Science Advances,
5(9)
Abstract:
GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
Abstract.
DOI.
Witherall L, Wagley S, Butler C, Tyler CR, Temperton B (2019). Genome Sequences of Four Vibrio parahaemolyticus Strains Isolated from the English Channel and the River Thames.
Microbiol Resour Announc,
8(24)
Abstract:
Genome Sequences of Four Vibrio parahaemolyticus Strains Isolated from the English Channel and the River Thames.
Vibrio parahaemolyticus is the lead causative agent for seafood-borne human gastroenteritis. While its occurrence has traditionally been uncommon in Europe and the United Kingdom, rising sea surface temperatures have resulted in an increased prevalence. Here, we present the complete genome sequences of four novel V. parahaemolyticus strains isolated in the United Kingdom.
Abstract.
Author URL.
DOI.
Studholme DJ, Panda P, Sanfuentes Von Stowasser E, González M, Hill R, Sambles C, Grant M, Williams NM, McDougal RL (2019). Genome sequencing of oomycete isolates from Chile supports the New Zealand origin of Phytophthora kernoviae and makes available the first Nothophytophthora sp. genome.
Mol Plant Pathol,
20(3), 423-431.
Abstract:
Genome sequencing of oomycete isolates from Chile supports the New Zealand origin of Phytophthora kernoviae and makes available the first Nothophytophthora sp. genome.
Genome sequences were generated for six oomycete isolates collected from forests in Valdivia, Chile. Three of the isolates were identified morphologically as Phytophthora kernoviae, whereas two were similar to other clade 10 Phytophthora species. One isolate was tentatively identified as Nothophytophthora valdiviana based on nucleotide sequence similarity in the cytochrome oxidase 1 gene. This is the first genome sequence for this recently described genus. The genome assembly was more fragmented and contained many duplicated genes when compared with the other Phytophthora sequences. Comparative analyses were performed with genomic sequences of the P. kernoviae isolates from the UK and New Zealand. Although the potential New Zealand origin of P. kernoviae has been suggested, new isolations from Chile had cast doubt on this hypothesis. We present evidence supporting P. kernoviae as having originated in New Zealand. However, investigation of the diversity of oomycete species in Chile has been limited and warrants further exploration. We demonstrate the expediency of genomic analyses in determining phylogenetic relationships between isolates within new and often scantly represented taxonomic groups, such as Phytophthora clade 10 and Nothophytophthora. Data are available on GenBank via BioProject accession number PRJNA352331.
Abstract.
Author URL.
DOI.
Green HD, Beaumont RN, Thomas A, Hamilton B, Wood AR, Sharp S, Jones SE, Tyrrell J, Walker G, Goodhand J, et al (2019). Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.
J Crohns Colitis,
13(12), 1578-1582.
Abstract:
Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.
BACKGROUND AND AIMS: the causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank. METHODS: in total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores. RESULTS: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis. CONCLUSIONS: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.
Abstract.
Author URL.
DOI.
Ji Y, Yiorkas AM, Frau F, Mook-Kanamori D, Staiger H, Thomas EL, Atabaki-Pasdar N, Campbell A, Tyrrell J, Jones SE, et al (2019). Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.
Diabetes,
68(1), 207-219.
Abstract:
Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.
Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.
Abstract.
Author URL.
DOI.
Jones SE, Lane JM, Wood AR, van Hees VT, Tyrrell J, Beaumont RN, Jeffries AR, Dashti HS, Hillsdon M, Ruth KS, et al (2019). Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.
Nature Communications Abstract:
Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.
Using genome-wide data from 697,828 UK Biobank and 23andMe participants, we increase the number of identified loci associated with being a morning person, a behavioural indicator of a person’s underlying circadian rhythm, from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we demonstrate that the chronotype loci influence sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 minutes earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.
Abstract.
DOI.
Schafmayer C, Harrison JW, Buch S, Lange C, Reichert MC, Hofer P, Cossais F, Kupcinskas J, von Schönfels W, Schniewind B, et al (2019). Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
Gut,
68(5), 854-865.
Abstract:
Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p
Abstract.
Author URL.
DOI.
Wang H, Lane JM, Jones SE, Dashti HS, Ollila HM, Wood AR, van Hees VT, Brumpton B, Winsvold BS, Kantojärvi K, et al (2019). Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.
Nature Communications,
10(1)
Abstract:
Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.
Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.
Abstract.
DOI.
Dashti HS, Jones SE, Wood AR, Lane JM, van Hees VT, Wang H, Rhodes JA, Song Y, Patel K, Anderson SG, et al (2019). Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
Nat Commun,
10(1)
Abstract:
Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration (p
Abstract.
Author URL.
DOI.
Ruth KS, Soares ALG, Borges M-C, Eliassen AH, Hankinson SE, Jones ME, Kraft P, Nichols HB, Sandler DP, Schoemaker MJ, et al (2019). Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan.
Hum Mol Genet,
28(8), 1392-1401.
Abstract:
Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan.
Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.
Abstract.
Author URL.
DOI.
Tamosauskaite J, Atkins J, Pilling L, Kuo C-L, Kuchel G, Ferrucci L, Melzer D (2019). Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain: Evidence from 200,975 Older UK Biobank Participants. Journals of Gerontology - Series a Biological Sciences and Medical Sciences
Richmond RC, Anderson EL, Dashti HS, Jones SE, Lane JM, Strand LB, Brumpton B, Rutter MK, Wood AR, Straif K, et al (2019). Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.
BMJ,
365 Abstract:
Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.
OBJECTIVE: to examine whether sleep traits have a causal effect on risk of breast cancer. DESIGN: Mendelian randomisation study. SETTING: UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study. PARTICIPANTS: 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis. EXPOSURES: Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits. MAIN OUTCOME MEASURE: Breast cancer diagnosis. RESULTS: in multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy. CONCLUSIONS: Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.
Abstract.
Author URL.
DOI.
Manley R, Temperton B, Doyle T, Gates D, Hedges S, Boots M, Wilfert L (2019). Knock-on community impacts of a novel vector: spillover of emerging DWV-B from Varroa-infested honeybees to wild bumblebees.
Ecol Lett,
22(8), 1306-1315.
Abstract:
Knock-on community impacts of a novel vector: spillover of emerging DWV-B from Varroa-infested honeybees to wild bumblebees.
Novel transmission routes can directly impact the evolutionary ecology of infectious diseases, with potentially dramatic effect on host populations and knock-on effects on the wider host community. The invasion of Varroa destructor, an ectoparasitic viral vector in Western honeybees, provides a unique opportunity to examine how a novel vector affects disease epidemiology in a host community. This specialist honeybee mite vectors deformed wing virus (DWV), an important re-emerging honeybee pathogen that also infects wild bumblebees. Comparing island honeybee and wild bumblebee populations with and without V. destructor, we show that V. destructor drives DWV prevalence and titre in honeybees and sympatric bumblebees. Viral genotypes are shared across hosts, with the potentially more virulent DWV-B overtaking DWV-A in prevalence in a current epidemic. This demonstrates disease emergence across a host community driven by the acquisition of a specialist novel transmission route in one host, with dramatic community level knock-on effects.
Abstract.
Author URL.
DOI.
Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland Ø, Laurin C, Bacelis J, Peng S, Hao K, Feenstra B, et al (2019). Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Nat Genet,
51(5), 804-814.
Abstract:
Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
Abstract.
Author URL.
DOI.
Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, Yengo L, Ferreira T, Marouli E, Ji Y, et al (2019). Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.
Hum Mol Genet,
28(1), 166-174.
Abstract:
Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.
More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.
Abstract.
Author URL.
DOI.
Tuke MA, Ruth KS, Wood AR, Beaumont RN, Tyrrell J, Jones SE, Yaghootkar H, Turner CLS, Donohoe ME, Brooke AM, et al (2019). Mosaic Turner syndrome shows reduced penetrance in an adult population study.
Genet Med,
21(4), 877-886.
Abstract:
Mosaic Turner syndrome shows reduced penetrance in an adult population study.
PURPOSE: Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the penetrance has been overestimated. METHODS: We characterized the prevalence and phenotypic consequences of X chromosome aneuploidy in a population of 244,848 women over 40 years of age from UK Biobank, using single-nucleotide polymorphism (SNP) array data. RESULTS: We detected 30 women with 45,X; 186 with mosaic 45,X/46,XX; and 110 with 47,XXX. The prevalence of nonmosaic 45,X (12/100,000) and 47,XXX (45/100,000) was lower than expected, but was higher for mosaic 45,X/46,XX (76/100,000). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognized Turner syndrome phenotype, including short stature and primary amenorrhea. In contrast, women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. The phenotype of women with 47,XXX included taller stature (5.3 cm; SD = 5.52 cm; P = 5.8 × 10-20) and earlier menopause age (5.12 years; SD = 5.1 years; P = 1.2 × 10-14). CONCLUSION: Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.
Abstract.
Author URL.
DOI.
Lines S, Mayne N, Manners J, Boutle I, Drummond B, Mikal-Evans T, Kohary K, Sing D (2019). Overcast on Osiris: 3D radiative-hydrodynamical simulations of a cloudy
hot Jupiter using the parametrized, phase-equilibrium cloud formation
code EDDYSED.
Monthly Notices of the Royal Astronomical Society,
488, 1332-1355.
DOI.
Young AK, Bate MR, Harries TJ, Acreman DM (2019). Synthetic molecular line observations of the first hydrostatic core from. chemical calculations.
Abstract:
Synthetic molecular line observations of the first hydrostatic core from. chemical calculations.
The first stable object to develop in the low-mass star formation process has
long been predicted to be the first hydrostatic core (FHSC). Despite much
effort, it has still yet to be definitively observed in nature. More specific
observational signatures are required to enable observers to distinguish the
FHSC from young, faint, but more evolved protostars. Here we present synthetic
spectral line observations for CO, SO, CS and HCO$^+$ that were calculated from
radiation (magneto)hydrodynamical models, chemical modelling and Monte Carlo
radiative transfer. HCO$^+$ $(1-0)$ and SO $(8_7 - 7_6)$ spectra of the FHSC
show variations for observations at a low inclination which may allow a
candidate FHSC to be distinguished from a more evolved object. We find that the
FHSC outflow is unlikely to be detectable with ALMA, which would discount the
observed sources with slow outflows that are currently identified as candidate
FHSCs. We compare the results of simulated ALMA observations with observed
candidate FHSCs and recommend Oph a SM1N and N6-mm as the most promising
candidates to follow up.
Abstract.
Author URL.
Kuo C-L, Pilling LC, Kuchel GA, Ferrucci L, Melzer D (2019). Telomere length and aging-related outcomes in humans: a Mendelian randomization study in 261,000 older participants.
Aging Cell,
18(6)
Abstract:
Telomere length and aging-related outcomes in humans: a Mendelian randomization study in 261,000 older participants.
Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks.
Abstract.
Author URL.
DOI.
Kikas T, Rull K, Beaumont RN, Freathy RM, Laan M (2019). The Effect of Genetic Variation on the Placental Transcriptome in Humans.
Frontiers in Genetics DOI.
Mayne NJ, Drummond B, Debras F, Jaupart E, Manners J, Boutle IA, Baraffe I, Kohary K (2019). The Limits of the Primitive Equations of Dynamics for Warm, Slowly Rotating Small Neptunes and Super Earths.
Astrophysical Journal,
871(1)
Abstract:
The Limits of the Primitive Equations of Dynamics for Warm, Slowly Rotating Small Neptunes and Super Earths.
We present significant differences in the simulated atmospheric flow for warm, tidally locked small Neptunes and super Earths (based on a nominal GJ 1214b) when solving the simplified, and commonly used, primitive dynamical equations or the full Navier-Stokes equations. The dominant prograde, superrotating zonal jet is markedly different between the simulations, which are performed using practically identical numerical setups, within the same model. The differences arise due to the breakdown of the so-called "shallow-fluid" and traditional approximations, which worsens when rotation rates are slowed, and day-night temperature contrasts are increased. The changes in the zonal advection between simulations solving the full and simplified equations, give rise to significant differences in the atmospheric redistribution of heat, altering the position of the hottest part of the atmosphere and temperature contrast between the daysides and nightsides. The implications for the atmospheric chemistry, and therefore, observations need to be studied with a model including a more detailed treatment of the radiative transfer and chemistry. Small Neptunes and super Earths are extremely abundant and important, potentially bridging the structural properties (mass, radius, and composition) of terrestrial and gas giant planets. Our results indicate care is required when interpreting the output of models solving the primitive equations of motion for such planets.
Abstract.
DOI.
Bate MR (2019). The statistical properties of stars and their dependence on metallicity.
Monthly Notices of the Royal Astronomical Society,
484(2), 2341-2361.
Abstract:
The statistical properties of stars and their dependence on metallicity.
We report the statistical properties of stars and brown dwarfs obtained from four radiation hydrodynamical simulations of star cluster formation, the metallicities of which span a range from 1/100 to 3 times the solar value. Unlike previous similar investigations of the effects of metallicity on stellar properties, these new calculations treat dust and gas temperatures separately and include a thermochemical model of the diffuse interstellar medium. The more advanced treatment of the interstellar medium gives rise to very different gas and dust temperature distributions in the four calculations, with lower metallicities generally resulting in higher temperatures and a delay in the onset of star formation. Despite this, once star formation begins, all four calculations produce stars at similar rates and many of the statistical properties of their stellar populations are difficult to distinguish from each other and from those of observed stellar systems. We do find, however, that the greater cooling rates at high gas densities due to the lower opacities at low metallicities increase the fragmentation on small spatial scales (disc, filament, and core fragmentation). This produces an anticorrelation between the close binary fraction of low-mass stars and metallicity similar to that which is observed, and an increase in the fraction of protostellar mergers at low metallicities. There are also indications that at lower metallicity close binaries may have lower mass ratios and the abundance of brown dwarfs to stars may increase slightly. However, these latter two effects are quite weak and need to be confirmed with larger samples.
Abstract.
DOI.
Wurster J, Bate MR, Price DJ (2019). There is no magnetic braking catastrophe: Low-mass star cluster and protostellar disc formation with non-ideal magnetohydrodynamics.
Monthly Notices of the Royal Astronomical Society,
489(2), 1719-1741.
Abstract:
There is no magnetic braking catastrophe: Low-mass star cluster and protostellar disc formation with non-ideal magnetohydrodynamics.
We present results from the first radiation non-ideal magnetohydrodynamics (MHD) simulations of low-mass star cluster formation that resolve the fragmentation process down to the opacity limit. We model 50 Mθ turbulent clouds initially threaded by a uniform magnetic field with strengths of 3, 5 10, and 20 times the critical mass-to-magnetic flux ratio, and at each strength, we model both an ideal and non-ideal (including Ohmic resistivity, ambipolar diffusion, and theHall effect)MHDcloud. Turbulence and magnetic fields shape the large-scale structure of the cloud, and similar structures form regardless of whether ideal or non-ideal MHD is employed. At high densities (106 ≲ nH ≲ 1011 cm-3), all models have a similar magnetic field strength versus density relation, suggesting that the field strength in dense cores is independent of the large-scale environment. Albeit with limited statistics, we find no evidence for the dependence of the initial mass function on the initial magnetic field strength, however, the star formation rate decreases for models with increasing initial field strengths; the exception is the strongest field case where collapse occurs primarily along field lines. Protostellar discs with radii ≳ 20 au form in all models, suggesting that disc formation is dependent on the gas turbulence rather than on magnetic field strength. We find no evidence for the magnetic braking catastrophe, and find that magnetic fields do not hinder the formation of protostellar discs.
Abstract.
DOI.
Tyrrell J, Mulugeta A, Wood AR, Zhou A, Beaumont RN, Tuke MA, Jones SE, Ruth KS, Yaghootkar H, Sharp S, et al (2019). Using genetics to understand the causal influence of higher BMI on depression.
Int J Epidemiol,
48(3), 834-848.
Abstract:
Using genetics to understand the causal influence of higher BMI on depression.
BACKGROUND: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. METHODS: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. RESULTS: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P
Abstract.
Author URL.
DOI.
Liu X, Helenius D, Skotte L, Beaumont RN, Wielscher M, Geller F, Juodakis J, Mahajan A, Bradfield JP, Lin FTJ, et al (2019). Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.
Nat Commun,
10(1)
Abstract:
Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.
The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Abstract.
Author URL.
DOI.
Bowman K, Jones L, Pilling LC, Delgado J, Kuchel GA, Ferrucci L, Fortinsky RH, Melzer D (2019). Vitamin D levels and risk of delirium: a mendelian randomization study in the UK Biobank.
Neurology DOI.
Frayling TM (2018). A Common Allele in FGF21 Associated with Sugar Intake is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure.
Cell Reports,
23(2), 327-336.
DOI.
Nakato GV, Wicker E, Coutinho TA, Mahuku G, Studholme DJ (2018). A highly specific tool for identification of Xanthomonas vasicola pv. musacearum based on five Xvm-specific coding sequences.
Heliyon,
4(12)
Abstract:
A highly specific tool for identification of Xanthomonas vasicola pv. musacearum based on five Xvm-specific coding sequences.
Xanthomonas vasicola pv. musacearum (Xvm) is a bacterial pathogen responsible for the economically important Xanthomonas wilt disease on banana and enset crops in Sub-Saharan Africa. Given that the symptoms are similar to those of other diseases, molecular diagnosis is essential to unambiguously identify this pathogen and distinguish it from closely related strains not pathogenic on these hosts. Currently, Xvm identification is based on polymerase chain reaction (PCR) with GspDm primers, targeting the gene encoding general secretory protein D. Experimental results and examination of genomic sequences revealed poor specificity of the GspDm PCR. Here, we present and validate five new Xvm-specific primers amplifying only Xvm strains.
Abstract.
DOI.
Kennedy P, Higginson AD, Radford AR, Sumner S (2018). Altruism in a volatile world.
Nature DOI.
Pilling LC, Masoli J, Melzer D, Kuchel G (2018). Clinical Outcomes of CADASIL-Associated NOTCH3 Mutations in 451,424 European Ancestry Community Volunteers.
Translational Stroke Research DOI.
Currie LK, Tobias SM (2018). Convection-driven kinematic dynamos with a self-consistent shear flow.
Geophysical & Astrophysical Fluid Dynamics,
113(1-2), 131-148.
DOI.
Michalopoulou VA, Vicente JG, Studholme DJ, Sarris PF (2018). Draft genome sequences of pathotype strains for three pathovars belonging to three xanthomonas species.
Microbiology Resource Announcements,
7(12)
Abstract:
Draft genome sequences of pathotype strains for three pathovars belonging to three xanthomonas species.
We present here the draft genome sequences of type/pathotype strains for three Xanthomonas species and pathovars with different host specificities, the Hedera helix L. pathogen Xanthomonas hortorum pv. hederae WHRI 7744 (NCPPB 939T), the rice pathogen X. oryzae pv. oryzicola WHRI 5234 (NCPPB 1585), and the cotton pathogen X. citri subsp. malvacearum WHRI 5232 (NCPPB 633).
Abstract.
DOI.
Schaum E, Buckling A, Studholme D, Smirnoff N, Yvon-Durocher G (2018). Environmental fluctuations accelerate molecular evolution of thermal tolerance in a marine diatom.
Nature Communications DOI.
van Hees VT, Sabia S, Jones SE, Wood AR, Anderson KN, Kivimaki M, Frayling TM, Pack AI, Bucan M, Trenell MI, et al (2018). Estimating sleep parameters using an accelerometer without sleep diary.
SCIENTIFIC REPORTS,
8 Author URL.
DOI.
Jun G, Manning A, Almeida M, Zawistowski M, Wood AR, Teslovich TM, Fuchsberger C, Feng S, Cingolani P, Gaulton KJ, et al (2018). Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.
Proc Natl Acad Sci U S A,
115(2), 379-384.
Abstract:
Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.
A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.
Abstract.
Author URL.
DOI.
Lines S, Manners J, Mayne NJ, Goyal J, Carter AL, Boutle IA, Lee EKH, Helling C, Drummond B, Acreman DM, et al (2018). Exonephology: Transmission spectra from a 3D simulated cloudy atmosphere. of HD209458b.
Abstract:
Exonephology: Transmission spectra from a 3D simulated cloudy atmosphere. of HD209458b.
We present high resolution transmission spectra, calculated directly from a
3D radiative-hydrodynamics simulation that includes kinetic cloud formation,
for HD209458b. We find that the high opacity of our vertically extensive cloud
deck, composed of a large number density of sub-micron particles, flattens the
transmission spectrum and obscures spectral features identified in observed
data. We use the PandExo simulator to explore features of our HD209458b
spectrum which may be detectable with the James Webb Space Telescope (JWST). We
determine that an 8 - 12 micron absorption feature attributed to the
mixed-composition, predominantly silicate cloud particles is a viable marker
for the presence of cloud. Further calculations explore, and trends are
identified with, variations in cloud opacity, composition heterogeneity and
artificially scaled gravitational settling on the transmission spectrum.
Principally, by varying the upper extent of our cloud decks, rainout is
identified to be a key process for the dynamical atmospheres of hot-Jupiters
and shown to dramatically alter the resulting spectrum. Our synthetic
transmission spectra, obtained from the most complete, forward atmosphere
simulations to--date, allow us to explore the model's ability to conform with
observations. Such comparisons can provide insight into the physical processes
either missing, or requiring improvement.
Abstract.
Author URL.
Boutle IA, Mayne NJ, Drummond B, Manners J, Goyal J, Lambert FH, Acreman DM, Earnshaw PD (2018). Exploring the climate of Proxima B with the Met Office Unified Model (corrigendum).
Astronomy and Astrophysics,
617 DOI.
Thomas NJ, Jones SE, Weedon MN, Shields BM, Oram RA, Hattersley AT (2018). Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank.
The Lancet Diabetes and Endocrinology,
6(2), 122-129.
Abstract:
Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank.
Background: Type 1 diabetes is typically considered a disease of children and young adults. Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes. It is not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years. We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life. Methods: in this cross-sectional analysis, we used a type 1 diabetes genetic risk score based on 29 common variants to identify individuals of white European descent in UK Biobank in the half of the population with high or low genetic susceptibility to type 1 diabetes. We used Kaplan-Meier analysis to evaluate the number of cases of diabetes in both groups in the first six decades of life. We genetically defined type 1 diabetes as the additional cases of diabetes that occurred in the high genetic susceptibility group compared with the low genetic susceptibility group. All remaining cases were defined as type 2 diabetes. We assessed the clinical characteristics of the groups with genetically defined type 1 or type 2 diabetes. Findings: 13 250 (3·5%) of 379 511 white European individuals in UK Biobank had developed diabetes in the first six decades of life. 1286 more cases of diabetes were in the half of the population with high genetic susceptibility to type 1 diabetes than in the half of the population with low genetic susceptibility. These genetically defined cases of type 1 diabetes were distributed across all ages of diagnosis; 537 (42%) were in individuals diagnosed when aged 31–60 years, representing 4% (537/12 233) of all diabetes cases diagnosed after age 30 years. The clinical characteristics of the group diagnosed with type 1 diabetes when aged 31–60 years were similar to the clinical characteristics of the group diagnosed with type 1 diabetes when aged 30 years or younger. For individuals diagnosed with diabetes when aged 31–60 years, the clinical characteristics of type 1 diabetes differed from those of type 2 diabetes: they had a lower BMI (27·4 kg/m2 [95% CI 26·7–28·0] vs 32·4 kg/m2 [32·2–32·5]; p
Abstract.
DOI.
Yemataw Z, Muzemil S, Ambachew D, Tripathi L, Tesfaye K, Chala A, Farbos A, O'Neill P, Moore K, Grant M, et al (2018). Genome sequence data from 17 accessions of Ensete ventricosum, a staple food crop for millions in Ethiopia.
Data in Brief,
18, 285-293.
Abstract:
Genome sequence data from 17 accessions of Ensete ventricosum, a staple food crop for millions in Ethiopia.
We present raw sequence reads and genome assemblies derived from 17 accessions of the Ethiopian orphan crop plant enset (Ensete ventricosum (Welw.) Cheesman) using the Illumina HiSeq and MiSeq platforms. Also presented is a catalogue of single-nucleotide polymorphisms inferred from the sequence data at an average density of approximately one per kilobase of genomic DNA.
Abstract.
DOI.
Morcrette H, Morgan MS, Farbos A, O'Neill P, Moore K, Titball RW, Studholme DJ (2018). Genome sequence of Staphylococcus aureus Ex1, isolated from a patient with spinal osteomyelitis.
Genome Announcements,
6(26)
Abstract:
Genome sequence of Staphylococcus aureus Ex1, isolated from a patient with spinal osteomyelitis.
Here, we present the genome sequence of Staphylococcus aureus Ex1, isolated in 2015 from a patient with spinal osteomyelitis at the Royal Devon and Exeter Hospital in the United Kingdom. The availability of the Ex1 genome sequence provides a resource for studying the basis for spinal infection and horizontal gene transfer in S. aureus.
Abstract.
DOI.
Nielsen JB, Fritsche LG, Zhou W, Teslovich TM, Holmen OL, Gustafsson S, Gabrielsen ME, Schmidt EM, Beaumont R, Wolford BN, et al (2018). Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development.
Am J Hum Genet,
102(1), 103-115.
Abstract:
Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development.
Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10-18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10-11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.
Abstract.
Author URL.
DOI.
Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, Geller F, Myhre R, Richmond RC, Paternoster L, et al (2018). Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
Hum Mol Genet,
27(4), 742-756.
Abstract:
Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P
Abstract.
Author URL.
DOI.
Wurster J, Bate MR, Price DJ (2018). Hall effect-driven formation of gravitationally unstable discs in. magnetized molecular cloud cores.
Abstract:
Hall effect-driven formation of gravitationally unstable discs in. magnetized molecular cloud cores.
We demonstrate the formation of gravitationally unstable discs in magnetized
molecular cloud cores with initial mass-to-flux ratios of 5 times the critical
value, effectively solving the magnetic braking catastrophe. We model the
gravitational collapse through to the formation of the stellar core, using
Ohmic resistivity, ambipolar diffusion and the Hall effect and using the
canonical cosmic ray ionization rate of $\zeta_\text{cr} = 10^{-17}$ s$^{-1}$.
When the magnetic field and rotation axis are initially aligned, a
$\lesssim1$~au disc forms after the first core phase, whereas when they are
anti-aligned, a gravitationally-unstable 25~au disc forms during the first core
phase. The aligned model launches a 3~km~s$^{-1}$ first core outflow, while the
anti-aligned model launches only a weak $\lesssim 0.3$~km~s$^{-1}$ first core
outflow. Qualitatively, we find that models with $\zeta_\text{cr} = 10^{-17}$
s$^{-1}$ are similar to purely hydrodynamical models if the rotation axis and
magnetic field are initially anti-aligned, whereas they are qualitatively
similar to ideal magnetohydrodynamical models if initially aligned.
Abstract.
Author URL.
Devran Z, Kahveci E, Hong Y, Studholme DJ, Tör M (2018). Identifying molecular markers suitable for Frl selection in tomato breeding.
Theor Appl Genet,
131(10), 2099-2105.
Abstract:
Identifying molecular markers suitable for Frl selection in tomato breeding.
Modern plant breeding heavily relies on the use of molecular markers. In recent years, next generation sequencing (NGS) emerged as a powerful technology to discover DNA sequence polymorphisms and generate molecular markers very rapidly and cost effectively, accelerating the plant breeding programmes. A single dominant locus, Frl, in tomato provides resistance to the fungal pathogen Fusarium oxysporum f. sp. radicis-lycopersici (FORL), causative agent of Fusarium crown and root rot. In this study, we describe the generation of molecular markers associated with the Frl locus. An F2 mapping population between an FORL resistant and a susceptible cultivar was generated. NGS technology was then used to sequence the genomes of a susceptible and a resistant parent as well the genomes of bulked resistant and susceptible F2 lines. We zoomed into the Frl locus and mapped the locus to a 900 kb interval on chromosome 9. Polymorphic single-nucleotide polymorphisms (SNPs) within the interval were identified and markers co-segregating with the resistant phenotype were generated. Some of these markers were tested successfully with commercial tomato varieties indicating that they can be used for marker-assisted selection in large-scale breeding programmes.
Abstract.
Author URL.
DOI.
Snowsill T, Yang H, Griffin E, Long L, Varley-Campbell J, Coelho H, Robinson S, Hyde C (2018). Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation.
Health Technology Assessment,
22(69), 1-276.
Abstract:
Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation.
Background: Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. Objectives: to estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations. Data sources: Bibliographic sources included MEDLINE, EMBASE, Web of Science and the Cochrane Library. Methods: Clinical effectiveness - a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and the Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness - an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm. Results: Clinical effectiveness - 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with ≤ 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost-effectiveness - screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60-75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in only a minority of analyses. Limitations: Clinical effectiveness - the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness - a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. Conclusions: LDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits.
Abstract.
DOI.
Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, Frayling TM, Hirschhorn J, Yang J, Visscher PM, et al (2018). Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry.
Hum Mol Genet,
27(20), 3641-3649.
Abstract:
Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry.
Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in ∼250000 European participants have led to the discovery of ∼700 and ∼100 nearly independent single nucleotide polymorphisms (SNPs) associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in ∼450000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N ∼700000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3290 and 941 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of P
Abstract.
Author URL.
DOI.
Minardi D, Studholme DJ, van der Giezen M, Pretto T, Oidtmann B (2018). New genotyping method for the causative agent of crayfish plague (Aphanomyces astaci) based on whole genome data.
Journal of Invertebrate Pathology,
156, 6-13.
Abstract:
New genotyping method for the causative agent of crayfish plague (Aphanomyces astaci) based on whole genome data.
The oomycete Aphanomyces astaci causes crayfish plague, the most important disease of European freshwater crayfish species. Presumably introduced into Europe 150 years ago with the import of North American crayfish, A. astaci is highly pathogenic to European crayfish species. Five genotypes (A, B, C, D, and E) have been defined based on random amplified polymorphic DNA analysis (RAPD-PCR) from A. astaci pure cultures. The distinction of genotypes is an essential tool to conduct molecular epidemiological studies on crayfish plague and it has been used to clarify and better understand the history and spread of this disease in Europe. Whereas RAPD-PCR requires DNA from pure culture isolates, the development of genotyping tools that can be applied to DNA extracted from clinical samples allows a much wider application of genotyping studies, including revisiting historic samples. In this study, we present a new approach that adds to currently available methods for genotyping A. astaci strains directly from clinical crayfish samples. Whole-genome sequencing of A. astaci strains representing all currently known genotypes was employed, genomic regions unique to the respective genotype identified, and a PCR-based genotyping assay designed, which focuses on the presence/absence of PCR product after amplification with the genotype-specific primers. Our diagnostic methodology was tested using DNA extracts from pure A. astaci cultures, other Aphanomyces species and additional oomycetes, samples from a recent Italian crayfish plague outbreak and additional historical samples available in the Centre for Environment, Fisheries and Aquaculture Science laboratory. The new markers were reliable for pure culture and clinical samples from a recent outbreak and successfully discriminated genotype A, B, D, and E. The marker for genotype C required an additional sequencing step of the generated PCR product to confirm genotype.
Abstract.
DOI.
Drummond B, Mayne NJ, Manners J, Carter AL, Boutle IA, Baraffe I, Hebrard E, Tremblin P, Sing DK, Amundsen DS, et al (2018). Observable signatures of wind--driven chemistry with a fully consistent. three dimensional radiative hydrodynamics model of HD 209458b.
Abstract:
Observable signatures of wind--driven chemistry with a fully consistent. three dimensional radiative hydrodynamics model of HD 209458b.
We present a study of the effect of wind-driven advection on the chemical
composition of hot Jupiter atmospheres using a fully-consistent 3D
hydrodynamics, chemistry and radiative transfer code, the Met Office Unified
Model (UM). Chemical modelling of exoplanet atmospheres has primarily been
restricted to 1D models that cannot account for 3D dynamical processes. In this
work we couple a chemical relaxation scheme to the UM to account for the
chemical interconversion of methane and carbon monoxide. This is done
consistently with the radiative transfer meaning that departures from chemical
equilibrium are included in the heating rates (and emission) and hence complete
the feedback between the dynamics, thermal structure and chemical composition.
In this letter we simulate the well studied atmosphere of HD~209458b. We find
that the combined effect of horizontal and vertical advection leads to an
increase in the methane abundance by several orders of magnitude; directly
opposite to the trend found in previous works. Our results demonstrate the need
to include 3D effects when considering the chemistry of hot Jupiter
atmospheres. We calculate transmission and emission spectra, as well as the
emission phase curve, from our simulations. We conclude that gas-phase
non-equilibrium chemistry is unlikely to explain the model-observation
discrepancy in the 4.5\,{\textmu m} {\it Spitzer}/IRAC channel. However, we
highlight other spectral regions, observable with the James Webb Space
Telescope, where signatures of wind-driven chemistry are more prominant.
Abstract.
Author URL.
Wurster J, Bate MR, Price DJ (2018). On the origin of magnetic fields in stars.
Abstract:
On the origin of magnetic fields in stars.
Are the kG-strength magnetic fields observed in young stars a fossil field
left over from their formation or are they generated by a dynamo? We use
radiation non-ideal magnetohydrodynamics simulations of the gravitational
collapse of a rotating, magnetized molecular cloud core over 17 orders of
magnitude in density, past the first hydrostatic core to the formation of the
second, stellar core, to examine the fossil field hypothesis. Whereas in
previous work we found that magnetic fields in excess of 10 kG can be implanted
in stars at birth, this assumed ideal magnetohydrodynamics (MHD), i.e. that the
gas is coupled to the magnetic field. Here we present non-ideal MHD
calculations which include Ohmic resistivity, ambipolar diffusion and the Hall
effect. For realistic cosmic ray ionization rates, we find that magnetic field
strengths of $\lesssim$ kG are implanted in the stellar core at birth, ruling
out a strong fossil field. While these results remain sensitive to resolution,
they cautiously provide evidence against a fossil field origin for stellar
magnetic fields, suggesting instead that magnetic fields in stars originate in
a dynamo process.
Abstract.
Author URL.
Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, et al (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Nat Genet,
50(1), 26-41.
Abstract:
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Abstract.
Author URL.
DOI.
Lines S, Mayne NJ, Boutle I, Manners J, Lee G, Helling C, Drummond B, Amundsen D, Goyal J, Acreman D, et al (2018). Simulating the cloudy atmospheres of HD 209458 b and HD 189733 b with the 3D Met Office Unified Model.
Astronomy and Astrophysics DOI.
Dobbs CL, Pettitt AR, Corbelli E, Pringle JE (2018). Simulations of the flocculent spiral M33: what drives the spiral structure?.
MONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY,
478(3), 3793-3808.
Author URL.
DOI.
Jones MO, Bate MR (2018). Sink particle radiative feedback in smoothed particle hydrodynamics models of star formation.
Monthly Notices of the Royal Astronomical Society DOI.
De Sanctis A, Amit I, Hepplestone S, Craciun M, Russo S (2018). Strain-engineered inverse charge-funnelling in layered semiconductors.
Nature Communications,
9 Abstract:
Strain-engineered inverse charge-funnelling in layered semiconductors.
The control of charges in a circuit due to an external electric field is
ubiquitous to the exchange, storage and manipulation of information in a wide range of applications, from electronic circuits to synapses in neural cells. Conversely, the ability to grow clean interfaces between materials has been a stepping stone for engineering built-in electric fields largely exploited in modern photovoltaics and opto-electronics. The emergence of atomically thin semiconductors is now enabling new ways to attain electric fields and unveil novel charge transport mechanisms. Here, we report the first direct electrical observation of the inverse charge-funnel effect enabled by deterministic and spatially resolved strain-induced electric fields in a thin sheet of HfS2. We demonstrate that charges driven by these spatially varying electric fields in the channel of a phototransistor lead to a 350% enhancement in the responsivity. These findings could enable the informed design of highly efficient photovoltaic cells.
Abstract.
DOI.
Drummond B, Mayne NJ, Manners J, Baraffe I, Goyal J, Tremblin P, Sing DK, Kohary K (2018). The 3D Thermal, Dynamical, and Chemical Structure of the Atmosphere of HD 189733b: Implications of Wind-driven Chemistry for the Emission Phase Curve.
Astrophysical Journal,
869(1)
Abstract:
The 3D Thermal, Dynamical, and Chemical Structure of the Atmosphere of HD 189733b: Implications of Wind-driven Chemistry for the Emission Phase Curve.
In this paper we present 3D atmospheric simulations of the hot Jupiter HD 189733b under two different scenarios: local chemical equilibrium and including advection of the chemistry by the resolved wind. Our model consistently couples the treatment of dynamics, radiative transfer, and chemistry, completing the feedback cycle between these three important processes. The effect of wind-driven advection on the chemical composition is qualitatively similar to our previous results for the warmer atmosphere of HD 209458b, found using the same model. However, we find more significant alterations to both the thermal and dynamical structure for the cooler atmosphere of HD 189733b, with changes in both the temperature and wind velocities reaching ∼10%. We also present the contribution function, diagnosed from our simulations, and show that wind-driven chemistry has a significant impact on its 3D structure, particularly for regions where methane is an important absorber. Finally, we present emission phase curves from our simulations and show the significant effect of wind-driven chemistry on the thermal emission, particularly within the 3.6 μm Spitzer/IRAC channel.
Abstract.
DOI.
Wurster JH, Bate MR, Price DJ (2018). The collapse of a molecular cloud core to stellar densities using radiation non-ideal magnetohydrodynamics.
MNRAS,
475, 1859-1880.
DOI.
Jones MO, Bate M (2018). The dependence of stellar properties on initial cloud density.
Monthly Notices of the Royal Astronomical Society,
478, 2650-2662.
DOI.
Mayne NJ, Drummond B, Baraffe I, Tremblin P, Manners J, Amundsen D, Goyal J, Acreman D (2018). The effect of metallicity on the atmospheres of exoplanets with fully coupled 3D hydrodynamics, equilibrium chemistry, and radiative transfer. Astronomy and Astrophysics
Higginson AD, Fawcett TW, Houston AI, McNamara JM (2018). Trust your gut: using physiological states as a source of information is almost as effective as optimal Bayesian learning.
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES,
285(1871)
Author URL.
DOI.
Wood AR, Jonsson A, Jackson AU, Wang N, van Leewen N, Palmer ND, Kobes S, Deelen J, Boquete-Vilarino L, Paananen J, et al (2017). A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.
Diabetes,
66(8), 2296-2309.
Abstract:
A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.
Abstract.
Author URL.
DOI.
Goyal JM, Mayne N, Sing DK, Drummond B, Tremblin P, Amundsen DS, Evans T, Carter AL, Spake J, Baraffe I, et al (2017). A library of ATMO forward model transmission spectra for hot Jupiter. exoplanets.
Monthly Notices of the Royal Astronomical Society, Volume 474. Issue 4, March 2018, Pages 5158-5185 Abstract:
A library of ATMO forward model transmission spectra for hot Jupiter. exoplanets.
We present a grid of forward model transmission spectra, adopting an
isothermal temperature-pressure profile, alongside corresponding equilibrium
chemical abundances for 117 observationally significant hot exoplanets
(Equilibrium Temperatures of 547-2710 K). This model grid has been developed
using a 1D radiative-convective-chemical equilibrium model termed ATMO, with
up-to-date high temperature opacities. We present an interpretation of
observations of ten exoplanets, including best fit parameters and $\chi^{2}$
maps. In agreement with previous works, we find a continuum from clear to
hazy/cloudy atmospheres for this sample of hot Jupiters. The data for all the
10 planets are consistent with sub-solar to solar C/O ratio, 0.005 to 10 times
solar metallicity and water rather than a methane dominated infrared spectra.
We then explore the range of simulated atmospheric spectra for different
exoplanets, based on characteristics such as temperature, metallicity,
C/O-ratio, haziness and cloudiness. We find a transition value for the
metallicity between 10 and 50 times solar, which leads to substantial changes
in the transmission spectra. We also find a transition value of C/O ratio, from
water to carbon species dominated infrared spectra, as found by previous works,
revealing a temperature dependence of this transition point ranging from
$\sim$0.56 to $\sim$1-1.3 for equilibrium temperatures from $\sim$900 to
$\sim$2600 K. We highlight the potential of the spectral features of HCN and
C$_2$H$_2$ to constrain the metallicities and C/O ratios of planets, using JWST
observations. Finally, our entire grid ($\sim$460,000 simulations) is publicly
available and can be used directly with the JWST simulator PandExo for planning
observations.
Abstract.
Author URL.
Macé A, Tuke MA, Deelen P, Kristiansson K, Mattsson H, Nõukas M, Sapkota Y, Schick U, Porcu E, Rüeger S, et al (2017). CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.
Nat Commun,
8(1)
Abstract:
CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.
There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g. MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
Abstract.
Author URL.
DOI.
Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, Saleheen D, Emdin C, Alam D, Alves AC, et al (2017). Exome-wide association study of plasma lipids in >300,000 individuals.
Nat Genet,
49(12), 1758-1766.
Abstract:
Exome-wide association study of plasma lipids in >300,000 individuals.
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
Abstract.
Author URL.
DOI.
Pratt J, Baraffe I, Goffrey T, Constantino T, Viallet M, Popov MV, Walder R, Folini D (2017). Extreme value statistics for two-dimensional convective penetration in a pre-main sequence star.
Astronomy and Astrophysics,
604 Abstract:
Extreme value statistics for two-dimensional convective penetration in a pre-main sequence star.
Context. In the interior of stars, a convectively unstable zone typically borders a zone that is stable to convection. Convective motions can penetrate the boundary between these zones, creating a layer characterized by intermittent convective mixing, and gradual erosion of the density and temperature stratification. Aims. We examine a penetration layer formed between a central radiative zone and a large convection zone in the deep interior of a young low-mass star. Using the Multidimensional Stellar Implicit Code (MUSIC) to simulate two-dimensional compressible stellar convection in a spherical geometry over long times, we produce statistics that characterize the extent and impact of convective penetration in this layer. Methods. We apply extreme value theory to the maximal extent of convective penetration at any time. We compare statistical results from simulations which treat non-local convection, throughout a large portion of the stellar radius, with simulations designed to treat local convection in a small region surrounding the penetration layer. For each of these situations, we compare simulations of different resolution, which have different velocity magnitudes. We also compare statistical results between simulations that radiate energy at a constant rate to those that allow energy to radiate from the stellar surface according to the local surface temperature. Results. Based on the frequency and depth of penetrating convective structures, we observe two distinct layers that form between the convection zone and the stable radiative zone. We show that the probability density function of the maximal depth of convective penetration at any time corresponds closely in space with the radial position where internal waves are excited. We find that the maximal penetration depth can be modeled by a Weibull distribution with a small shape parameter. Using these results, and building on established scalings for diffusion enhanced by large-scale convective motions, we propose a new form for the diffusion coefficient that may be used for one-dimensional stellar evolution calculations in the large Péclet number regime. These results should contribute to the 321D link.
Abstract.
DOI.
Hepplestone SP, Taylor NT, Davies F (2017). First principles electronic and elastic properties of fresnoite Ba2TiSi2O8.
Materials Research Express,
4, 125904-125904.
Abstract:
First principles electronic and elastic properties of fresnoite Ba2TiSi2O8.
Electronic, structural and elastic properties of fresnoite, Ba2TiSi2O8 (BTSO), are obtained via first principles calculations. The electronic properties having been comparatively analysed using both the generalised gradient approximation and the hybrid functional method. The indirect band gap of BTSO is found to change significantly through the choice of functional; it shows an increase from 3.79 eV to 5.72 eV. A small indirect gap of 0.33 eV is also present directly above the conduction band edge, which allows for small optical transitions similar to that of defect transitions. The titanium orbitals are dominant near the conduction band edge, with oxygen orbitals being the main contributor to the valence band edge. Dielectric and elastic properties of the material are also obtained, with the bulk modulus being 131.73 GPa and the elastic moduli along the [1 0 0] and [0 0 1] directions being 180.57 GPa and 102.56 GPa, respectively. Theoretical values for Raman frequencies are reported for BTSO. Finally, Bader charge analysis reveals the barium and titanium atoms in BTSO are comparable to their charges in BaTiO3. However, due to the presence of the Si–O bonds, oxygen exhibits a significant charge redistribution. Through the choice of functional, charge can become more localised on the oxygen atoms.
Abstract.
DOI.
Tyrrell J, Wood AR, Ames RM, Yaghootkar H, Beaumont RN, Jones SE, Tuke MA, Ruth KS, Freathy RM, Davey Smith G, et al (2017). Gene-obesogenic environment interactions in the UK Biobank study.
Int J Epidemiol,
46(2), 559-575.
Abstract:
Gene-obesogenic environment interactions in the UK Biobank study.
BACKGROUND: Previous studies have suggested that modern obesogenic environments accentuate the genetic risk of obesity. However, these studies have proven controversial as to which, if any, measures of the environment accentuate genetic susceptibility to high body mass index (BMI). METHODS: We used up to 120 000 adults from the UK Biobank study to test the hypothesis that high-risk obesogenic environments and behaviours accentuate genetic susceptibility to obesity. We used BMI as the outcome and a 69-variant genetic risk score (GRS) for obesity and 12 measures of the obesogenic environment as exposures. These measures included Townsend deprivation index (TDI) as a measure of socio-economic position, TV watching, a 'Westernized' diet and physical activity. We performed several negative control tests, including randomly selecting groups of different average BMIs, using a simulated environment and including sun-protection use as an environment. RESULTS: We found gene-environment interactions with TDI (Pinteraction = 3 × 10 -10 ), self-reported TV watching (Pinteraction = 7 × 10 -5 ) and self-reported physical activity (Pinteraction = 5 × 10 -6 ). Within the group of 50% living in the most relatively deprived situations, carrying 10 additional BMI-raising alleles was associated with approximately 3.8 kg extra weight in someone 1.73 m tall. In contrast, within the group of 50% living in the least deprivation, carrying 10 additional BMI-raising alleles was associated with approximately 2.9 kg extra weight. The interactions were weaker, but present, with the negative controls, including sun-protection use, indicating that residual confounding is likely. CONCLUSIONS: Our findings suggest that the obesogenic environment accentuates the risk of obesity in genetically susceptible adults. of the factors we tested, relative social deprivation best captures the aspects of the obesogenic environment responsible.
Abstract.
Author URL.
DOI.
Sollars ESA, Harper AL, Kelly LJ, Sambles CM, Ramirez-Gonzalez RH, Swarbreck D, Kaithakottil G, Cooper ED, Uauy C, Havlickova L, et al (2017). Genome sequence and genetic diversity of European ash trees.
Nature,
541(7636), 212-216.
Abstract:
Genome sequence and genetic diversity of European ash trees.
Ash trees (genus Fraxinus, family Oleaceae) are widespread throughout the Northern Hemisphere, but are being devastated in Europe by the fungus Hymenoscyphus fraxineus, causing ash dieback, and in North America by the herbivorous beetle Agrilus planipennis. Here we sequence the genome of a low-heterozygosity Fraxinus excelsior tree from Gloucestershire, UK, annotating 38,852 protein-coding genes of which 25% appear ash specific when compared with the genomes of ten other plant species. Analyses of paralogous genes suggest a whole-genome duplication shared with olive (Olea europaea, Oleaceae). We also re-sequence 37 F. excelsior trees from Europe, finding evidence for apparent long-term decline in effective population size. Using our reference sequence, we re-analyse association transcriptomic data, yielding improved markers for reduced susceptibility to ash dieback. Surveys of these markers in British populations suggest that reduced susceptibility to ash dieback may be more widespread in Great Britain than in Denmark. We also present evidence that susceptibility of trees to H. fraxineus is associated with their iridoid glycoside levels. This rapid, integrated, multidisciplinary research response to an emerging health threat in a non-model organism opens the way for mitigation of the epidemic.
Abstract.
Author URL.
DOI.
Turner J, O'Neill P, Grant M, Mumford RA, Thwaites R, Studholme DJ (2017). Genome sequences of 12 isolates of the EU1 lineage of Phytophthora ramorum , a fungus-like pathogen that causes extensive damage and mortality to a wide range of trees and other plants.
Genomics Data,
12, 17-21.
DOI.
Pilling LC, Kuo C-L, Sicinski K, Tamosauskaite J, Kuchel GA, Harries LW, Herd P, Wallace R, Ferrucci L, Melzer D, et al (2017). Human longevity: 25 genetic loci associated in 389,166 UK biobank participants.
Aging (Albany NY),
9(12), 2504-2520.
Abstract:
Human longevity: 25 genetic loci associated in 389,166 UK biobank participants.
We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p
Abstract.
Author URL.
DOI.
Baraffe I, Pratt J, Goffrey T, Constantino T, Folini D, Popov MV, Walder R, Viallet M (2017). Lithium Depletion in Solar-like Stars: Effect of Overshooting Based on Realistic Multi-dimensional Simulations.
Astrophysical Journal Letters,
845(1)
Abstract:
Lithium Depletion in Solar-like Stars: Effect of Overshooting Based on Realistic Multi-dimensional Simulations.
We study lithium depletion in low-mass and solar-like stars as a function of time, using a new diffusion coefficient describing extra-mixing taking place at the bottom of a convective envelope. This new form is motivated by multi-dimensional fully compressible, time-implicit hydrodynamic simulations performed with the MUSIC code. Intermittent convective mixing at the convective boundary in a star can be modeled using extreme value theory, a statistical analysis frequently used for finance, meteorology, and environmental science. In this Letter, we implement this statistical diffusion coefficient in a one-dimensional stellar evolution code, using parameters calibrated from multi-dimensional hydrodynamic simulations of a young low-mass star. We propose a new scenario that can explain observations of the surface abundance of lithium in the Sun and in clusters covering a wide range of ages, from ∼50 Myr to ∼4 Gyr. Because it relies on our physical model of convective penetration, this scenario has a limited number of assumptions. It can explain the observed trend between rotation and depletion, based on a single additional assumption, namely, that rotation affects the mixing efficiency at the convective boundary. We suggest the existence of a threshold in stellar rotation rate above which rotation strongly prevents the vertical penetration of plumes and below which rotation has small effects. In addition to providing a possible explanation for the long-standing problem of lithium depletion in pre-main-sequence and main-sequence stars, the strength of our scenario is that its basic assumptions can be tested by future hydrodynamic simulations.
Abstract.
DOI.
Vicente JG, Rothwell S, Holub EB, Studholme DJ (2017). Pathogenic, phenotypic and molecular characterisation of Xanthomonas nasturtii sp. nov. and Xanthomonas floridensis sp. nov. new species of Xanthomonas associated with watercress production in Florida.
Int J Syst Evol Microbiol,
67(9), 3645-3654.
Abstract:
Pathogenic, phenotypic and molecular characterisation of Xanthomonas nasturtii sp. nov. and Xanthomonas floridensis sp. nov. new species of Xanthomonas associated with watercress production in Florida.
We describe two new species of the genus Xanthomonas, represented by yellow mucoid bacterial strains isolated from diseased leaves of watercress (Nasturtium officinale) produced in Florida, USA. One strain was pathogenic on watercress, but not in other species including a range of brassicas; other strains were not pathogenic in any of the tested plants. Data from Biolog carbon source utilization tests and nucleotide sequence data from 16S and gyrB loci suggested that both pathogenic and non-pathogenic strains were related to, yet distinct from, previously described Xanthomonas species. Multilocus sequence analysis and whole genome-wide comparisons of the average nucleotide identity (ANI) of genomes of two strains from watercress showed that these are distinct and share less than 95 % ANI with all other known species; the non-pathogenic strain WHRI 8848 is close to Xanthomonascassavae (ANI of 93.72 %) whilst the pathogenic strain WHRI 8853 is close to a large clade of species that includes Xanthomonasvesicatoria (ANI ≤90.25 %). Based on these results, we propose that both strains represent new Xanthomonas species named Xanthomonas floridensis sp. nov. (type strain WHRI 8848=ATCC TSD-60=ICMP 21312=LMG 29665=NCPPB 4601) and Xanthomonas nasturtii sp. nov. (type strain WHRI 8853=ATCC TSD-61=ICMP 21313=LMG 29666=NCPPB 4600), respectively. The presence of non-pathogenic Xanthomonas strains in watercress and their interaction with pathogenic strains needs to be further investigated. Although the importance of the new pathogenic species is yet to be determined, the bacterial disease that it causes constitutes a threat to watercress production and its distribution should be monitored.
Abstract.
Author URL.
DOI.
Yaghootkar H, Bancks MP, Jones SE, McDaid A, Beaumont R, Donnelly L, Wood AR, Campbell A, Tyrrell J, Hocking LJ, et al (2017). Quantifying the extent to which index event biases influence large genetic association studies.
Hum Mol Genet,
26(5), 1018-1030.
Abstract:
Quantifying the extent to which index event biases influence large genetic association studies.
As genetic association studies increase in size to 100 000s of individuals, subtle biases may influence conclusions. One possible bias is 'index event bias' (IEB) that appears due to the stratification by, or enrichment for, disease status when testing associations between genetic variants and a disease-associated trait. We aimed to test the extent to which IEB influences some known trait associations in a range of study designs and provide a statistical framework for assessing future associations. Analyzing data from 113 203 non-diabetic UK Biobank participants, we observed three (near TCF7L2, CDKN2AB and CDKAL1) overestimated (body mass index (BMI) decreasing) and one (near MTNR1B) underestimated (BMI increasing) associations among 11 type 2 diabetes risk alleles (at P < 0.05). IEB became even stronger when we tested a type 2 diabetes genetic risk score composed of these 11 variants (-0.010 standard deviations BMI per allele, P = 5 × 10- 4), which was confirmed in four additional independent studies. Similar results emerged when examining the effect of blood pressure increasing alleles on BMI in normotensive UK Biobank samples. Furthermore, we demonstrated that, under realistic scenarios, common disease alleles would become associated at P < 5 × 10- 8 with disease-related traits through IEB alone, if disease prevalence in the sample differs appreciably from the background population prevalence. For example, some hypertension and type 2 diabetes alleles will be associated with BMI in sample sizes of >500 000 if the prevalence of those diseases differs by >10% from the background population. In conclusion, IEB may result in false positive or negative genetic associations in very large studies stratified or strongly enriched for/against disease cases.
Abstract.
Author URL.
DOI.
Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C, Highland HM, et al (2017). Rare and low-frequency coding variants alter human adult height.
Nature,
542(7640), 186-190.
Abstract:
Rare and low-frequency coding variants alter human adult height.
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
Abstract.
Author URL.
DOI.
Pilling LC, Atkins JL, Duff MO, Beaumont RN, Jones SE, Tyrrell J, Kuo C-L, Ruth KS, Tuke MA, Yaghootkar H, et al (2017). Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.
PLoS One,
12(9)
Abstract:
Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.
INTRODUCTION: Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. RESULTS: a large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%,
Abstract.
Author URL.
DOI.
Goffrey T, Pratt J, Viallet M, Baraffe I, Popov MV, Walder R, Folini D, Geroux C, Constantino T (2016). Benchmarking the Multi-dimensional Stellar Implicit Code MUSIC.
Abstract:
Benchmarking the Multi-dimensional Stellar Implicit Code MUSIC.
We present the results of a numerical benchmark study for the
MUlti-dimensional Stellar Implicit Code (MUSIC) based on widely applicable two-
and three-dimensional compressible hydrodynamics problems relevant to stellar
interiors. MUSIC is an implicit large eddy simulation code that uses implicit
time integration, implemented as a Jacobian-free Newton Krylov method. A
physics based preconditioning technique which can be adjusted to target varying
physics is used to improve the performance of the solver. The problems used for
this benchmark study include the Rayleigh-Taylor and Kelvin-Helmholtz
instabilities, and the decay of the Taylor-Green vortex. Additionally we show a
test of hydrostatic equilibrium, in a stellar environment which is dominated by
radiative effects. In this setting the flexibility of the preconditioning
technique is demonstrated. This work aims to bridge the gap between the
hydrodynamic test problems typically used during development of numerical
methods and the complex flows of stellar interiors. A series of
multi-dimensional tests are performed and analysed. Each of these test cases is
analysed with a simple, scalar diagnostic, with the aim of enabling direct code
comparisons. As the tests performed do not have analytic solutions we verify
MUSIC by comparing to established codes including ATHENA and the PENCIL code.
MUSIC is able to both reproduce behaviour from established and widely-used
codes as well as results expected from theoretical predictions. This
benchmarking study concludes a series of papers describing the development of
the MUSIC code and provides confidence in the future applications.
Abstract.
Author URL.
Tyrrell J, Richmond RC, Palmer TM, Feenstra B, Rangarajan J, Metrustry S, Cavadino A, Paternoster L, Armstrong LL, De Silva NMG, et al (2016). Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.
JAMA,
315(11), 1129-1129.
DOI.
Yaghootkar H, Lotta LA, Tyrrell J, Smit RAJ, Jones SE, Donnelly L, Beaumont R, Campbell A, Tuke MA, Hayward C, et al (2016). Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease.
Diabetes,
65(8), 2448-2460.
Abstract:
Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease.
Recent genetic studies have identified some alleles that are associated with higher BMI but lower risk of type 2 diabetes, hypertension, and heart disease. These "favorable adiposity" alleles are collectively associated with lower insulin levels and higher subcutaneous-to-visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, to test for interactions between BMI and favorable adiposity genetics, and to test effects separately in men and women. In the UK Biobank, the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 kg/m(2) [95% CI 0.066, 0.174]; P = 1E-5) and higher body fat percentage (0.301% [0.230, 0.372]; P = 1E-16) compared with the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favorable adiposity alleles were at lower risk of type 2 diabetes (odds ratio [OR] 0.837 [0.784, 0.894]; P = 1E-7), hypertension (OR 0.935 [0.911, 0.958]; P = 1E-7), and heart disease (OR 0.921 [0.872, 0.973]; P = 0.003) and had lower blood pressure (systolic -0.859 mmHg [-1.099, -0.618]; P = 3E-12 and diastolic -0.394 mmHg [-0.534, -0.254]; P = 4E-8). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favorable body fat distribution, with a lower waist-to-hip ratio (-0.004 cm [95% CI -0.005, -0.003] 50% vs. 50%; P = 3E-14), but in men, the favorable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267, 0.641] 50% vs. 50%; P = 2E-6) and higher waist-to-hip ratio (0.0013 [0.0003, 0.0024] 50% vs. 50%; P = 0.01). Results were strengthened when a meta-analysis with five additional studies was conducted. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score. In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. Although higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.
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Ruth KS, Beaumont RN, Tyrrell J, Jones SE, Tuke MA, Yaghootkar H, Wood AR, Freathy RM, Weedon MN, Frayling TM, et al (2016). Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.
Hum Reprod,
31(2), 473-481.
Abstract:
Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.
STUDY QUESTION: How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health? SUMMARY ANSWER: the T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis. WHAT IS KNOWN ALREADY: the FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle. MAIN RESULTS AND THE ROLE OF CHANCE: the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12-0.20; P = 6 × 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 × 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 × 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 × 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 × 10(-9)). LIMITATIONS, REASONS FOR CAUTION: the data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as 'irregular'). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect. WIDER IMPLICATIONS OF THE FINDINGS: We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.
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Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, Feenstra B, Van Zuydam NR, Gaulton KJ, Grarup N, et al (2016). Genome-wide associations for birth weight and correlations with adult disease.
Nature,
538(7624), 248-252.
Abstract:
Genome-wide associations for birth weight and correlations with adult disease.
© 2016 Macmillan Publishers Limited, part of Springer Nature. Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P. <. 5 × 10 -8 ). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R g =-0.22, P = 5.5 × 10 -13 ), T2D (R g =-0.27, P = 1.1 × 10 -6 ) and coronary artery disease (R g =-0.30, P = 6.5 × 10 -9 ). In addition, using large-cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
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Kilpeläinen TO, Carli JFM, Skowronski AA, Sun Q, Kriebel J, Feitosa MF, Hedman ÅK, Drong AW, Hayes JE, Zhao J, et al (2016). Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.
Nat Commun,
7 Abstract:
Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P
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Pilling LC, Atkins JL, Bowman K, Jones SE, Tyrrell J, Beaumont RN, Ruth KS, Tuke MA, Yaghootkar H, Wood AR, et al (2016). Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
Aging (Albany NY),
8(3), 547-560.
Abstract:
Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.
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Wood AR, Tyrrell J, Beaumont R, Jones SE, Tuke MA, Ruth KS, GIANT consortium, Yaghootkar H, Freathy RM, Murray A, et al (2016). Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively.
Diabetologia,
59(6), 1214-1221.
Abstract:
Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively.
AIMS/HYPOTHESIS: Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases. METHODS: We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity. RESULTS: Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p DOMDEV = 3 × 10(-5)) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m(2), 27.54 (95% CI 27.50, 27.58) kg/m(2) and 28.07 (95% CI 28.00, 28.14) kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p DOMDEV = 0.003; meta-analysis p DOMDEV = 1 × 10(-7)). For type 2 diabetes, we detected a recessive effect (p DOMDEV = 5 × 10(-4)) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance. CONCLUSIONS/INTERPRETATION: Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci. ACCESS TO RESEARCH MATERIALS: Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.
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Usher CL, Handsaker RE, Esko T, Tuke MA, Weedon MN, Hastie AR, Cao H, Moon JE, Kashin S, Fuchsberger C, et al (2015). Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity.
Nat Genet,
47(8), 921-925.
Abstract:
Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity.
Hundreds of genes reside in structurally complex, poorly understood regions of the human genome. One such region contains the three amylase genes (AMY2B, AMY2A and AMY1) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity, although genome-wide association studies for obesity have found this locus unremarkable. Using whole-genome sequence analysis, droplet digital PCR and genome mapping, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling ∼3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI, yet found no association.
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