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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.
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.
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.
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.
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.
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 Â 10 À8 . 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.
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.
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.
The key empirical property of the X-ray emission from O stars is a strong correlation between the bolometric and X-ray luminosities. In the framework of the Chandra Carina Complex Project, 129 O and B stars have been detected as X-ray sources; 78 of those, all with spectral type earlier than B3, have enough counts for at least a rough X-ray spectral characterization. This leads to an estimate of the L-X-L-BOL ratio for an exceptional number of 60 O stars belonging to the same region and triples the number of Carina massive stars studied spectroscopically in X-rays. The derived log(L-X/L-BOL) is -7.26 for single objects, with a dispersion of only 0.21 dex. Using the properties of hot massive stars listed in the literature, we compare the X-ray luminosities of different types of objects. In the case of O stars, the L-X-L-BOL ratios are similar for bright and faint objects, as well as for stars of different luminosity classes or spectral types. Binaries appear only slightly harder and slightly more luminous in X-rays than single objects; the differences are not formally significant (at the 1% level), except for the L-X-L-BOL ratio in the medium (1.0-2.5 keV) energy band. Weak-wind objects have similar X-ray luminosities but they display slightly softer spectra compared with "normal" O stars with the same bolometric luminosity. Discarding three overluminous objects, we find a very shallow trend of harder emission in brighter objects. The properties of the few B stars bright enough to yield some spectral information appear to be different overall (constant X-ray luminosities, harder spectra), hinting that another mechanism for producing X-rays, besides wind shocks, might be at work. However, it must be stressed that the earliest and X-ray brightest among these few detected objects are similar to the latest O stars, suggesting a possibly smooth transition between the two processes.
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.
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.
We report on both high-precision photometry from the Microvariability and Oscillations of Stars (MOST) space telescope and ground-based spectroscopy of the triple system delta Ori A, consisting of a binary O9.5II+early-B (Aa1 and Aa2) with P = 5.7 days, and a more distant tertiary (O9 IV P > 400 years). This data was collected in concert with X-ray spectroscopy from the Chandra X-ray Observatory. Thanks to continuous coverage for three weeks, the MOST light curve reveals clear eclipses between Aa1 and Aa2 for the first time in non-phased data. From the spectroscopy, we have a well-constrained radial velocity (RV) curve of Aa1. While we are unable to recover RV variations of the secondary star, we are able to constrain several fundamental parameters of this system and determine an approximate mass of the primary using apsidal motion. We also detected second order modulations at 12 separate frequencies with spacings indicative of tidally influenced oscillations. These spacings have never been seen in a massive binary, making this system one of only a handful of such binaries that show evidence for tidally induced pulsations.
The Chandra Carina Complex contains 200 known O- and B-type stars. The Chandra survey detected 68 of the 70 O stars and 61 of 127 known B0-B3 stars. We have assembled a publicly available optical/X-ray database to identify OB stars that depart from the canonical L-X/L-bol relation or whose average X-ray temperatures exceed 1 keV. Among the single O stars with high kT we identify two candidate magnetically confined wind shock sources: Tr16-22, O8.5 V, and LS 1865, O8.5 V((f)). The O4 III(fc) star HD 93250 exhibits strong, hard, variable X-rays, suggesting that it may be a massive binary with a period of > 30 days. The visual O2 If* binary HD 93129A shows soft 0.6 keV and hard 1.9 keV emission components, suggesting embedded wind shocks close to the O2 If* Aa primary and colliding wind shocks between Aa and Ab. Of the 11 known O-type spectroscopic binaries, the long orbital-period systems HD 93343, HD 93403, and QZ Car have higher shock temperatures than short-period systems such as HD 93205 and FO 15. Although the X-rays from most B stars may be produced in the coronae of unseen, low-mass pre-main-sequence companions, a dozen B stars with high L-X cannot be explained by a distribution of unseen companions. One of these, SS73 24 in the Treasure Chest cluster, is a new candidate Herbig Be star.