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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.
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.
River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth’s biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented “next-generation biomonitoring” by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.
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.
Geothermobarometric, radiogenic isotopic and thermochronologic data are used to track the influence of an ancient continental margin (Western Province) on development of an adjacent Carboniferous-Cretaceous magmatic arc (Outboard Median Batholith) in Fiordland, New Zealand. The data show a record of complicated Mesozoic Gondwana margin growth. Paragneiss within the Outboard Median Batholith is of Carboniferous to Jurassic age and records burial to middle crustal depths in Late Jurassic-Early Cretaceous during subduction-related plutonism and arc thickening. In contrast, Western Province metasedimentary rocks in the area of study immediately west of the Outboard Median Batholith are Late Cambrian-Early Ordovician in age, recrystallized at the amphibolite facies in the Late Devonian-Early Carboniferous and exhibit no evidence for Mesozoic textural or isotopic reequilibration. A phase of deformation, between 128 and 116 Ma deformed, exhumed, and cooled the Outboard Median Batholith to greenschist facies temperatures, while large parts of the Western Province underwent >= 9 kbar metamorphic conditions. Zircon grains from Mesozoic inboard plutons are isotopically more evolved (epsilon Hf(t) = +2.3 to +4.0) than those in the Outboard Median Batholith (epsilon Hf(t) = +9.4 to +11.1). The contrasting zircon Hf isotope ratios, absence of S-type plutons or Proterozoic-Early Paleozoic inherited zircon, and the apparent absence of Early Paleozoic metasedimentary rocks indicates that the Outboard Median Batholith is unlikely to be underlain by the Western Province continental lithosphere. The new data are consistent with the Outboard Median Batholith representing an allochthonous (although not necessarily exotic) arc that was juxtaposed onto the Gondwana continental margin along the intervening Grebe Mylonite Zone.
Extremely rare veinlets and reaction textures composed of symplectites of olivine (similar to Fo(43-55)) + plagioclase +/- spinel +/- ilmenite, associated with more common pyroxene + plagioclase and amphibole + plagioclase varieties, are preserved within eclogites and garnet pyroxenites in the Moldanubian Zone of the Bohemian Massif. Thermodynamic modelling integrated with conventional geothermometry conducted on an eclogite reveals that the symplectite-forming stage occurred at high T (similar to 850 degrees C) and low P (< 6 and > 2 center dot 5 kbar). The development of the different symplectite types reflects reactions that took place in micro-scale domains. The breakdown of high-P garnet controlled the formation of olivine-bearing and amphibole + plagioclase symplectites, whereas breakdown of high-P omphacite led to formation of pyroxene + plagioclase symplectites. In addition, post-eclogite facies but pre-symplectite stage porphyroblastic amphibole and phlogopite were also replaced by olivine-bearing symplectites. Material transfer calculations and thermodynamic modelling indicate that the formation of different symplectite types was linked despite their different bulk compositions. For example, the olivine-bearing symplectites gained Fe +/- Mg, whereas adjacent amphibole + plagioclase and pyroxene + plagioclase symplectites show losses in Fe and Mg; Al, Si and Ca were also variably exchanged. The olivine-bearing symplectites were particularly sensitive to Na despite the small concentration of this element. In eclogites where Na was readily available, the plagioclase composition in the olivine-bearing symplectites shifted from pure anorthite to bytownite, with the less calcic feldspar partitioning Si and inhibiting the formation of orthopyroxene. This regional high-T, low-P granulite-facies symplectite overprint may have been caused by advective heat loss from rapidly exhumed high-T, high-P granulitic bodies (Gfohl Unit) that were emplaced into and over the middle crust (Monotonous and Varied Series) during Carboniferous continent-continent collision.
Newly determined Late Cretaceous Ar-40/Ar-39 ages on megacrystic kaersutite from four lamprophyre dikes, and a U-Pb zircon age on a trachyte, from central and north Westland (New Zealand) are presented. These ages suggest that the intrusion of mafic dikes (88-86 and 69 Ma) was not necessarily restricted to the previously established narrow age range of 80-92 Ma. The younger lamprophyre and trachyte dikes (c. 68-70 Ma) imply that tensional stresses in the Western Province were either renewed at this time, or that extension and related magmatism continued during opening of the Tasman Sea. Extension-related magmatism in the region not only preceded Tasman seafloor spreading initiation (starting at c. 83 Ma, lasting to c. 53 Ma), but may have sporadically continued for up to 15 Ma after continental break-up.
This study pushes our understanding of research reliability by reproducing and replicating claims from 110 papers in leading economic and political science journals. The analysis involves computational reproducibility checks and robustness assessments. It reveals several patterns. First, we uncover a high rate of fully computationally reproducible results (over 85%). Second, excluding minor issues like missing packages or broken pathways, we uncover coding errors for about 25% of studies, with some studies containing multiple errors. Third, we test the robustness of the results to 5,511 re-analyses. We find a robustness reproducibility of about 70%. Robustness reproducibility rates are relatively higher for re-analyses that introduce new data and lower for re-analyses that change the sample or the definition of the dependent variable. Fourth, 52% of re-analysis effect size estimates are smaller than the original published estimates and the average statistical significance of a re-analysis is 77% of the original. Lastly, we rely on six teams of researchers working independently to answer eight additional research questions on the determinants of robustness reproducibility. Most teams find a negative relationship between replicators' experience and reproducibility, while finding no relationship between reproducibility and the provision of intermediate or even raw data combined with the necessary cleaning codes.