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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.
Sedimentary ancient DNA has been proposed as a key methodology for reconstructing biodiversity over time. Yet, despite the concentration of Earth’s biodiversity in the tropics, this method has rarely been applied in this region. Moreover, the taphonomy of sedimentary DNA, especially in tropical environments, is poorly understood. This study elucidates challenges and opportunities of sedimentary ancient DNA approaches for reconstructing tropical biodiversity. We present shotgun-sequenced metagenomic profiles and DNA degradation patterns from multiple sediment cores from Mubwindi Swamp, located in Bwindi Impenetrable Forest (Uganda), one of the most diverse forests in Africa. We describe the taxonomic composition of the sediments covering the past 2200 years and compare the sedimentary DNA data with a comprehensive set of environmental and sedimentological parameters to unravel the conditions of DNA degradation. Consistent with the preservation of authentic ancient DNA in tropical swamp sediments, DNA concentration and mean fragment length declined exponentially with age and depth, while terminal deamination increased with age. DNA preservation patterns cannot be explained by any environmental parameter alone, but age seems to be the primary driver of DNA degradation in the swamp. Besides degradation, the presence of living microbial communities in the sediment also affects DNA quantity. Critically, 92.3% of our metagenomic data of a total 81.8 million unique, merged reads cannot be taxonomically identified due to the absence of genomic references in public databases. Of the remaining 7.7%, most of the data (93.0%) derive from Bacteria and Archaea, whereas only 0–5.8% are from Metazoa and 0–6.9% from Viridiplantae, in part due to unbalanced taxa representation in the reference data. The plant DNA record at ordinal level agrees well with local pollen data but resolves less diversity. Our animal DNA record reveals the presence of 41 native taxa (16 orders) including Afrotheria, Carnivora, and Ruminantia at Bwindi during the past 2200 years. Overall, we observe no decline in taxonomic richness with increasing age suggesting that several-thousand-year-old information on past biodiversity can be retrieved from tropical sediments. However, comprehensive genomic surveys of tropical biota need prioritization for sedimentary DNA to be a viable methodology for future tropical biodiversity studies.
Sedimentary ancient DNA has been proposed as a key methodology for reconstructing biodiversity over time. Yet, despite the concentration of Earth’s biodiversity in the tropics, this method has rarely been applied in this region. Moreover, the taphonomy of sedimentary DNA, especially in tropical environments, is poorly understood. This study elucidates challenges and opportunities of sedimentary ancient DNA approaches for reconstructing tropical biodiversity. We present shotgun-sequenced metagenomic profiles and DNA degradation patterns from multiple sediment cores from Mubwindi Swamp, located in Bwindi Impenetrable Forest (Uganda), one of the most diverse forests in Africa. We describe the taxonomic composition of the sediments covering the past 2200 years and compare the sedimentary DNA data with a comprehensive set of environmental and sedimentological parameters to unravel the conditions of DNA degradation. Consistent with the preservation of authentic ancient DNA in tropical swamp sediments, DNA concentration and mean fragment length declined exponentially with age and depth, while terminal deamination increased with age. DNA preservation patterns cannot be explained by any environmental parameter alone, but age seems to be the primary driver of DNA degradation in the swamp. Besides degradation, the presence of living microbial communities in the sediment also affects DNA quantity. Critically, 92.3% of our metagenomic data of a total 81.8 million unique, merged reads cannot be taxonomically identified due to the absence of genomic references in public databases. Of the remaining 7.7%, most of the data (93.0%) derive from Bacteria and Archaea, whereas only 0–5.8% are from Metazoa and 0–6.9% from Viridiplantae, in part due to unbalanced taxa representation in the reference data. The plant DNA record at ordinal level agrees well with local pollen data but resolves less diversity. Our animal DNA record reveals the presence of 41 native taxa (16 orders) including Afrotheria, Carnivora, and Ruminantia at Bwindi during the past 2200 years. Overall, we observe no decline in taxonomic richness with increasing age suggesting that several-thousand-year-old information on past biodiversity can be retrieved from tropical sediments. However, comprehensive genomic surveys of tropical biota need prioritization for sedimentary DNA to be a viable methodology for future tropical biodiversity studies.