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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 11 July 1889 Chilik earthquake (M-w 8.0-8.3) forms part of a remarkable sequence of large earthquakes in the late nineteenth and early twentieth centuries in the northern Tien Shan. Despite its importance, the source of the 1889 earthquake remains unknown, though the macroseismic epicenter is sited in the Chilik valley, similar to 100 km southeast of Almaty, Kazakhstan (similar to 2 million population). Several short fault segments that have been inferred to have ruptured in 1889 are too short on their own to account for the estimated magnitude. In this paper we perform detailed surveying and trenching of the similar to 30 km long Saty fault, one of the previously inferred sources, and find that it was formed in a single earthquake within the last 700 years, involving surface slip of up to 10 m. The scarp-forming event, likely to be the 1889 earthquake, was the only surface-rupturing event for at least 5000 years and potentially for much longer. From satellite imagery we extend the mapped length of fresh scarps within the 1889 epicentral zone to a total of similar to 175 km, which we also suggest as candidate ruptures from the 1889 earthquake. The 175 km of rupture involves conjugate oblique left-lateral and right-lateral slip on three separate faults, with step overs of several kilometers between them. All three faults were essentially invisible in the Holocene geomorphology prior to the last slip. The recurrence interval between large earthquakes on any of these faults, and presumably on other faults of the Tien Shan, may be longer than the timescale over which the landscape is reset, providing a challenge for delineating sources of future hazard.
People with the genetic disorder of Williams syndrome (WS) show an anomalous cognitive profile, wherein some purely verbal and social communicative abilities are relatively proficient, while visuo-spatial skills can be extremely impaired. Face processing, while apparently relatively spared among visuo-spatial skills, can show deficits suggesting developmental immaturity. In this context, the exploration of visual and audiovisual speech perception in WS is of interest. A new test based on tokens from a single natural English speaker of the form /ba:/, /va:/, /tha:/, /da:/ and / ga:/, digitally manipulated and presented in unimodal (vision alone, audition alone) and audiovisual conditions, was presented for participants to identify each token. Compared with age-matched controls, WS participants were impaired at visual but not auditory identification, and in audiovisual testing showed correspondingly reduced effects of vision on report of auditory token identity. Audiovisual integration was nevertheless demonstrable in WS. Speech-reading may require skills which do not reach age-appropriate levels in WS, despite their age-appropriate (auditory) phonological abilities.
Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades
(2017)
Food system innovations will be instrumental to achieving multiple Sustainable Development Goals (SDGs). However, major innovation breakthroughs can trigger profound and disruptive changes, leading to simultaneous and interlinked reconfigurations of multiple parts of the global food system. The emergence of new technologies or social solutions, therefore, have very different impact profiles, with favourable consequences for some SDGs and unintended adverse side-effects for others. Stand-alone innovations seldom achieve positive outcomes over multiple sustainability dimensions. Instead, they should be embedded as part of systemic changes that facilitate the implementation of the SDGs. Emerging trade-offs need to be intentionally addressed to achieve true sustainability, particularly those involving social aspects like inequality in its many forms, social justice, and strong institutions, which remain challenging. Trade-offs with undesirable consequences are manageable through the development of well planned transition pathways, careful monitoring of key indicators, and through the implementation of transparent science targets at the local level.
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.