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.
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.
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.
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 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.
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 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.