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- quasars: absorption lines (4)
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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.
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.
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.
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.
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.
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.