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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.
AimAdvancement in ecological methods predicting species distributions is a crucial precondition for deriving sound management actions. Maximum entropy (MaxEnt) models are a popular tool to predict species distributions, as they are considered able to cope well with sparse, irregularly sampled data and minor location errors. Although a fundamental assumption of MaxEnt is that the entire area of interest has been systematically sampled, in practice, MaxEnt models are usually built from occurrence records that are spatially biased towards better-surveyed areas. Two common, yet not compared, strategies to cope with uneven sampling effort are spatial filtering of occurrence data and background manipulation using environmental data with the same spatial bias as occurrence data. We tested these strategies using simulated data and a recently collated dataset on Malay civet Viverra tangalunga in Borneo.
LocationBorneo, Southeast Asia.
MethodsWe collated 504 occurrence records of Malay civets from Borneo of which 291 records were from 2001 to 2011 and used them in the MaxEnt analysis (baseline scenario) together with 25 environmental input variables. We simulated datasets for two virtual species (similar to a range-restricted highland and a lowland species) using the same number of records for model building. As occurrence records were biased towards north-eastern Borneo, we investigated the efficacy of spatial filtering versus background manipulation to reduce overprediction or underprediction in specific areas.
ResultsSpatial filtering minimized omission errors (false negatives) and commission errors (false positives). We recommend that when sample size is insufficient to allow spatial filtering, manipulation of the background dataset is preferable to not correcting for sampling bias, although predictions were comparatively weak and commission errors increased.
Main ConclusionsWe conclude that a substantial improvement in the quality of model predictions can be achieved if uneven sampling effort is taken into account, thereby improving the efficacy of species conservation planning.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Background. The bay cat Catopuma badia is endemic to Borneo, whereas its sister species the Asian golden cat Catopuma temminckii is distributed from the Himalayas and southern China through Indochina, Peninsular Malaysia and Sumatra. Based onmorphological data, up to five subspecies of the Asian golden cat have been recognized, but a taxonomic assessment, including molecular data and morphological characters, is still lacking. Results. We combined molecular data (whole mitochondrial genomes), morphological data (pelage) and species distribution projections (up to the Late Pleistocene) to infer how environmental changes may have influenced the distribution of these sister species over the past 120 000 years. The molecular analysis was based on sequenced mitogenomes of 3 bay cats and 40 Asian golden cats derived mainly from archival samples. Our molecular data suggested a time of split between the two species approximately 3.16 Ma and revealed very low nucleotide diversity within the Asian golden cat population, which supports recent expansion of the population. Discussion. The low nucleotide diversity suggested a population bottleneck in the Asian golden cat, possibly caused by the eruption of the Toba volcano in Northern Sumatra (approx. 74 kya), followed by a continuous population expansion in the Late Pleistocene/Early Holocene. Species distribution projections, the reconstruction of the demographic history, a genetic isolation-by-distance pattern and a gradual variation of pelage pattern support the hypothesis of a post-Toba population expansion of the Asian golden cat from south China/Indochina to PeninsularMalaysia and Sumatra. Our findings reject the current classification of five subspecies for the Asian golden cat, but instead support either a monotypic species or one comprising two subspecies: (i) the Sunda golden cat, distributed south of the Isthmus of Kra: C. t. temminckii and (ii) Indochinese, Indian, Himalayan and Chinese golden cats, occurring north of the Isthmus: C. t. moormensis.
Rapid population growth and economic development have led to increased anthropogenic pressures on the Tibetan Plateau, causing significant land cover changes with potentially severe ecological consequences. To assess whether or not these pressures are also affecting the remote montane-boreal lakes on the SE Tibetan Plateau, fossil pollen and diatom data from two lakes were synthesized. The interplay of aquatic and terrestrial ecosystem response was explored in respect to climate variability and human activity over the past 200 years. Nonmetric multidimensional scaling and Procrustes rotation analysis were undertaken to determine whether pollen and diatom responses in each lake were similar and synchronous. Detrended canonical correspondence analysis was used to develop quantitative estimates of compositional species turnover. Despite instrumental evidence of significant climatic warming on the southeastern Plateau, the pollen and diatom records indicate very stable species composition throughout their profiles and show only very subtle responses to environmental changes over the past 200 years. The compositional species turnover (0.36-0.94 SD) is relatively low in comparison to the species reorganizations known from the periods during the mid-and early-Holocene (0.64-1.61 SD) on the SE Plateau, and also in comparison to turnover rates of sediment records from climate-sensitive regions in the circum arctic. Our results indicate that climatically induced ecological thresholds are not yet crossed, but that human activity has an increasing influence, particularly on the terrestrial ecosystem in our study area. Synergistic processes of post-Little Ice Age warming, 20th century climate warming and extensive reforestations since the 19th century have initiated a change from natural oak-pine forests to seminatural, likely less resilient pine-oak forests. Further warming and anthropogenic disturbances would possibly exceed the ecological threshold of these ecosystems and lead to severe ecological consequences.
Grenzen sind immanenter Bestandteil der internationalen Beziehungen. Deren Kern besteht ja darin, dass Akteure über (nationalstaatliche) Grenzen hinweg handeln. Die Grenze und deren Überschreitung sind somit eine conditio sine qua non von internationalen Beziehungen. Das stellt sich in Europa, Amerika und Afrika sehr verschieden dar und wird auch unterschiedlich diskutiert. Der vorliegende Band bildet dies ab: die theoretische Debatte und die empirische Verschiedenheit in den Regionen, wobei die Europäische Union den regionalen Schwerpunkt bildet. Der vorliegende Band, der auf einen Lehrtext von 2005 aufbaut, enthält neue Texte zu Amerika und zu Europas Ostgrenze.