To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Introducing the CTA concept
(2013)
The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project.
A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia
(2019)
The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
We present an accurate analysis of the H-2 absorption lines from the z(abs) similar to 2.4018 damped Ly alpha system towards HE 0027-1836 observed with the Very Large Telescope Ultraviolet and Visual Echelle Spectrograph (VLT/UVES) as a part of the European Southern Observatory Large Programme 'The UVES large programme for testing fundamental physics' to constrain the variation of proton-to-electron mass ratio, mu m(p)/m(e). We perform cross-correlation analysis between 19 individual exposures taken over three years and the combined spectrum to check the wavelength calibration stability. We notice the presence of a possible wavelength-dependent velocity drift especially in the data taken in 2012. We use available asteroids spectra taken with UVES close to our observations to confirm and quantify this effect. We consider single-and two-component Voigt profiles to model the observed H-2 absorption profiles. We use both linear regression analysis and Voigt profile fitting where Delta mu/mu is explicitly considered as an additional fitting parameter. The two-component model is marginally favoured by the statistical indicators and we get Delta mu/mu = -2.5 +/- 8.1(stat) +/- 6.2(sys) ppm. When we apply the correction to the wavelength-dependent velocity drift, we find Delta mu/mu = -7.6 +/- 8.1(stat) +/- 6.3(sys) ppm. It will be important to check the extent to which the velocity drift we notice in this study is present in UVES data used for previous Delta mu/mu measurements.
Context. Absorption-line systems detected in quasar spectra can be used to compare the value of the fine-structure constant, alpha, measured today on Earth with its value in distant galaxies. In recent years, some evidence has emerged of small temporal and also spatial variations in alpha on cosmological scales. These variations may reach a fractional level of approximate to 10 ppm (parts per million).
Aims. To test these claims we are conducting a Large Program of observations with the Very Large Telescope's Ultraviolet and Visual Echelle Spectrograph (UVES), and are obtaining high-resolution (R approximate to 60 000) and high signal-to-noise ratio (S/N approximate to 100) UVES spectra calibrated specifically for this purpose. Here we analyse the first complete quasar spectrum from this programme, that of HE 2217-2818.
Methods. We applied the many multiplet method to measure alpha in five absorption systems towards this quasar: z(abs) = 0.7866, 0.9424, 1.5558, 1.6279, and 1.6919.
Results. The most precise result is obtained for the absorber at z(abs) = 1.6919 where 3 Fe II transitions and Al II lambda 1670 have high S/N and provide a wide range of sensitivities to alpha. The absorption profile is complex with several very narrow features, and it requires 32 velocity components to be fitted to the data. We also conducted a range of tests to estimate the systematic error budget. Our final result for the relative variation in alpha in this system is Delta alpha/alpha = +1.3 +/- 2.4(stat) +/- 1.0(sys) ppm. This is one of the tightest current bounds on alpha-variation from an individual absorber. A second, separate approach to the data reduction, calibration, and analysis of this system yielded a slightly different result of -3.8 +/- 2.1(stat) ppm, possibly suggesting a larger systematic error component than our tests indicated. This approach used an additional 3 Fe II transitions, parts of which were masked due to contamination by telluric features. Restricting this analysis to the Fe II transitions alone and using a modified absorption profile model gave a result that is consistent with the first approach, Delta alpha/alpha = +1.1 +/- 2.6(stat) ppm. The four other absorbers have simpler absorption profiles, with fewer and broader features, and offer transitions with a narrower range of sensitivities to alpha. They therefore provide looser bounds on Delta alpha/alpha at the greater than or similar to 10 ppm precision level.
Conclusions. The absorbers towards quasar HE 2217-2818 reveal no evidence of any variation in alpha at the 3-ppm precision level (1 sigma confidence). If the recently reported 10-ppm dipolar variation in alpha across the sky is correct, the expectation at this sky position is (3.2-5.4) +/- 1.7 ppm depending on dipole model used. Our constraint of Delta alpha/alpha = +1.3 +/- 2.4(stat) +/- 1.0(sys) ppm is not inconsistent with this expectation.
A novel common variant in DCST2 is associated with length in early life and height in adulthood
(2015)
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Myriapods (e. g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.
We present an overview of four deep phase-constrained Chandra HETGS X-ray observations of delta Ori A. Delta Ori A is actually a triple system that includes the nearest massive eclipsing spectroscopic binary, delta Ori Aa, the only such object that can be observed with little phase-smearing with the Chandra gratings. Since the fainter star, delta Ori Aa2, has a much lower X-ray luminosity than the brighter primary (delta Ori Aa1), delta Ori Aa provides a unique system with which to test the spatial distribution of the X-ray emitting gas around delta Ori Aa1 via occultation by the photosphere of, and wind cavity around, the X-ray dark secondary. Here we discuss the X-ray spectrum and X-ray line profiles for the combined observation, having an exposure time of nearly 500 ks and covering nearly the entire binary orbit. The companion papers discuss the X-ray variability seen in the Chandra spectra, present new space-based photometry and ground-based radial velocities obtained simultaneously with the X-ray data to better constrain the system parameters, and model the effects of X-rays on the optical and UV spectra. We find that the X-ray emission is dominated by embedded wind shock emission from star Aa1, with little contribution from the tertiary star Ab or the shocked gas produced by the collision of the wind of Aa1 against the surface of Aa2. We find a similar temperature distribution to previous X-ray spectrum analyses. We also show that the line half-widths are about 0.3-0.5 times the terminal velocity of the wind of star Aa1. We find a strong anti-correlation between line widths and the line excitation energy, which suggests that longer-wavelength, lower-temperature lines form farther out in the wind. Our analysis also indicates that the ratio of the intensities of the strong and weak lines of Fe XVII and Ne X are inconsistent with model predictions, which may be an effect of resonance scattering.
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.
We introduce a new survey of massive stars in the Galaxy and the Magellanic Clouds using the Fibre Large Array Multi- Element Spectrograph ( FLAMES) instrument at the Very Large Telescope ( VLT). Here we present observations of 269 Galactic stars with the FLAMES- Giraffe Spectrograph ( R similar or equal to 25 000), in fields centered on the open clusters NGC3293, NGC4755 and NGC6611. These data are supplemented by a further 50 targets observed with the Fibre- Fed Extended Range Optical Spectrograph ( FEROS, R = 48 000). Following a description of our scientific motivations and target selection criteria, the data reduction methods are described; of critical importance the FLAMES reduction pipeline is found to yield spectra that are in excellent agreement with less automated methods. Spectral classifications and radial velocity measurements are presented for each star, with particular attention paid to morphological peculiarities and evidence of binarity. These observations represent a significant increase in the known spectral content of NGC3293 and NGC4755, and will serve as standards against which our subsequent FLAMES observations in the Magellanic Clouds will be compared
Recent reports of increasing iron (Fe) concentrations in freshwaters are of concern, given the fundamental role of Fe in biogeochemical processes. Still, little is known about the frequency and geographical distribution of Fe trends or about the underlying drivers. We analyzed temporal trends of Fe concentrations across 340 water bodies distributed over 10 countries in northern Europe and North America in order to gain a clearer understanding of where, to what extent, and why Fe concentrations are on the rise. We found that Fe concentrations have significantly increased in 28% of sites, and decreased in 4%, with most positive trends located in northern Europe. Regions with rising Fe concentrations tend to coincide with those with organic carbon (OC) increases. Fe and OC increases may not be directly mechanistically linked, but may nevertheless be responding to common regional-scale drivers such as declining sulfur deposition or hydrological changes. A role of hydrological factors was supported by covarying trends in Fe and dissolved silica, as these elements tend to stem from similar soil depths. A positive relationship between Fe increases and conifer cover suggests that changing land use and expanded forestry could have contributed to enhanced Fe export, although increases were also observed in nonforested areas. We conclude that the phenomenon of increasing Fe concentrations is widespread, especially in northern Europe, with potentially significant implications for wider ecosystem biogeochemistry, and for the current browning of freshwaters.
We present time-resolved and phase-resolved variability studies of an extensive X-ray high-resolution spectral data set of the delta Ori Aa binary system. The four observations, obtained with Chandra ACIS HETGS, have a total exposure time of approximate to 479 ks and provide nearly complete binary phase coverage. Variability of the total X-ray flux in the range of 5-25 is is confirmed, with a maximum amplitude of about +/- 15% within a single approximate to 125 ks observation. Periods of 4.76 and 2.04 days are found in the total X-ray flux, as well as an apparent overall increase in the flux level throughout the nine-day observational campaign. Using 40 ks contiguous spectra derived from the original observations, we investigate the variability of emission line parameters and ratios. Several emission lines are shown to be variable, including S XV, Si XIII, and Ne IX. For the first time, variations of the X-ray emission line widths as a function of the binary phase are found in a binary system, with the smallest widths at phi = 0.0 when the secondary delta Ori Aa2 is at the inferior conjunction. Using 3D hydrodynamic modeling of the interacting winds, we relate the emission line width variability to the presence of a wind cavity created by a wind-wind collision, which is effectively void of embedded wind shocks and is carved out of the X-ray-producing primary wind, thus producing phase-locked X-ray variability.
The Great Nebula in Carina provides an exceptional view into the violent massive star formation and feedback that typifies giant H II regions and starburst galaxies. We have mapped the Carina star-forming complex in X-rays, using archival Chandra data and a mosaic of 20 new 60 ks pointings using the Chandra X-ray Observatory's Advanced CCD Imaging Spectrometer, as a testbed for understanding recent and ongoing star formation and to probe Carina's regions of bright diffuse X-ray emission. This study has yielded a catalog of properties of > 14,000 X-ray point sources;> 9800 of them have multiwavelength counterparts. Using Chandra's unsurpassed X-ray spatial resolution, we have separated these point sources from the extensive, spatially-complex diffuse emission that pervades the region; X-ray properties of this diffuse emission suggest that it traces feedback from Carina's massive stars. In this introductory paper, we motivate the survey design, describe the Chandra observations, and present some simple results, providing a foundation for the 15 papers that follow in this special issue and that present detailed catalogs, methods, and science results.
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< 5 x 10(-8). In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
Atlantic Meridional Overturning Circulation (AMOC) projections are uncertain due to both model errors, as well as internal climate variability. An AMOC slowdown projected by many climate models is likely to have considerable effects on many aspects of global and North Atlantic climate. Previous studies to make probabilistic AMOC projections have broken new ground. However, they do not drift-correct or cross-validate the projections, and do not fully account for internal variability. Furthermore, they consider a limited subset of models, and ignore the skill of models at representing the temporal North Atlantic dynamics. We improve on previous work by applying Bayesian Model Averaging to weight 13 Coupled Model Intercomparison Project phase 5 models by their skill at modeling the AMOC strength, and its temporal dynamics, as approximated by the northern North-Atlantic temperature-based AMOC Index. We make drift-corrected projections accounting for structural model errors, and for the internal variability. Cross-validation experiments give approximately correct empirical coverage probabilities, which validates our method. Our results present more evidence that AMOC likely already started slowing down. While weighting considerably moderates and sharpens our projections, our results are at low end of previously published estimates. We project mean AMOC changes between periods 1960-1999 and 2060-2099 of -4.0 Sv and -6.8 Sv for RCP4.5 and RCP8.5 emissions scenarios respectively. The corresponding average 90% credible intervals for our weighted experiments are [-7.2, -1.2] and [-10.5, -3.7] Sv respectively for the two scenarios.
Context. The Tarantula Nebula (a.k.a. 30 Dor) is a spectacular star-forming region in the Large Magellanic Cloud (LMC), seen through gas in the Galactic disc and halo. Diffuse interstellar bands (DIBs) offer a unique probe of the diffuse, cool-warm gas in these regions.
Aims. The aim is to use DIBs as diagnostics of the local interstellar conditions, whilst at the same time deriving properties of the yet-unknown carriers of these enigmatic spectral features.
Methods. Spectra of over 800 early-type stars from the Very Large Telescope Flames Tarantula Survey (VFTS) were analysed. Maps were created, separately, for the Galactic and LMC absorption in the DIBs at 4428 and 6614 angstrom and - in a smaller region near the central cluster R 136 - neutral sodium (the Na ID doublet); we also measured the DIBs at 5780 and 5797 angstrom.
Results. The maps show strong 4428 and 6614 angstrom DIBs in the quiescent cloud complex to the south of 30 Dor but weak absorption in the harsher environments to the north (bubbles) and near the OB associations. The Na maps show at least five kinematic components in the LMC and a shell-like structure surrounding R 136, and small-scale structure in the Milky Way. The strengths of the 4428, 5780, 5797 and 6614 angstrom DIBs are correlated, also with Na absorption and visual extinction. The strong 4428 angstrom DIB is present already at low Na column density but the 6614, 5780 and 5797 angstrom DIBs start to be detectable at subsequently larger Na column densities.
Conclusions. The carriers of the 4428, 6614, 5780 and 5797 angstrom DIBs are increasingly prone to removal from irradiated gas. The relative strength of the 5780 and 5797 angstrom DIBs clearly confirm the Tarantula Nebula as well as Galactic high-latitude gas to represent a harsh radiation environment. The resilience of the 4428 angstrom DIB suggests its carrier is large, compact and neutral. Structure is detected in the distribution of cool-warm gas on scales between one and > 100 pc in the LMC and as little as 0.01 pc in the Sun's vicinity. Stellar winds from the central cluster R 136 have created an expanding shell; some infalling gas is also detected, reminiscent of a galactic "fountain".