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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 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.
Lyman limit systems (LLSs) trace the low-density circumgalactic medium and the most dense regions of the intergalactic medium, so their number density and evolution at high-redshift, just after reionization, are important to constrain. We present a survey for LLSs at high redshifts, z(LLS) = 3.5-5.4, in the homogeneous data set of 153 optical quasar spectra at z similar to 5 from the Giant Gemini GMOS survey. Our analysis includes detailed investigation of survey biases using mock spectra which provide important corrections to the raw measurements. We estimate the incidence of LLSs per unit redshift at z approximate to 4.4 to be l(z) = 2.6 +/- 0.4. Combining our results with previous surveys at z(LLS) < 4, the best-fit power-law evolution is l(z) = l(*)[(1 + z)/4](alpha) with l* = 1.46 +/- 0.11 and alpha = 1.70 +/- 0.22 (68 per cent confidence intervals). Despite hints in previous z(LLS) < 4 results, there is no indication for a deviation from this single power-law soon after reionization. Finally, we integrate our new results with previous surveys of the intergalactic and circumgalactic media to constrain the hydrogen column density distribution function, f(N-HI, X), over 10 orders ofmagnitude. The data at z similar to 5 are not well-described by the f(N-HI, X) model previously reported for z similar to 2-3 (after re-scaling) and a 7-pivot model fitting the full z similar to 2-5 data set is statistically unacceptable. We conclude that there is significant evolution in the shape of f(N-HI, X) over this similar to 2-billion-year period.
NGTS-5b
(2019)
Context. Planetary population analysis gives us insight into formation and evolution processes. For short-period planets, the sub-Jovian desert has been discussed in recent years with regard to the planet population in the mass/period and radius/period parameter space without taking stellar parameters into account. The Next Generation Transit Survey (NGTS) is optimised for detecting planets in this regime, which allows for further analysis of the sub-Jovian desert. Aims. With high-precision photometric surveys (e.g. with NGTS and TESS), which aim to detect short period planets especially around M/K-type host stars, stellar parameters need to be accounted for when empirical data are compared to model predictions. Presenting a newly discovered planet at the boundary of the sub-Jovian desert, we analyse its bulk properties and use it to show the properties of exoplanets that border the sub-Jovian desert. Methods. Using NGTS light curve and spectroscopic follow-up observations, we confirm the planetary nature of planet NGTS-5b and determine its mass. Using exoplanet archives, we set the planet in context with other discoveries. Results. NGTS-5b is a short-period planet with an orbital period of 3.3569866 +/- 0.0000026 days. With a mass of 0.229 +/- 0.037 M-Jup and a radius of 1.136 +/- 0.023 R-Jup, it is highly inflated. Its mass places it at the upper boundary of the sub-Jovian desert. Because the host is a K2 dwarf, we need to account for the stellar parameters when NGTS-5b is analysed with regard to planet populations. Conclusions. With red-sensitive surveys (e.g. with NGTS and TESS), we expect many more planets around late-type stars to be detected. An empirical analysis of the sub-Jovian desert should therefore take stellar parameters into account.