Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Variant annotation was supported by software resources provided via the Caché Campus program of the InterSystems GmbH to Alexander Teumer

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.Peer reviewe

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics

Hatchability of African Catfish Clarias gariepinus Eggs in Hapas and in Basins: a Diagnostic Study of Frequent Inhibition by Rainfall and Water Stagnation

To diagnose inhibition of egg hatchability by rainfall and water stagnation, some incubating eggs were protected against the physical impact of raindrops, some were subjected to various turbidity levels and others, to various incubation densities (number of eggs/litre of water) in flowing vs. stagnant water. Data analyses showed that, unaffected by raindrops (P> 0.05), hatchability was inversely proportional to both turbidity (coefficient= -0.971) and incubation density (coefficient= -0.973). Only the properly constructed ponds (i.e., with elevated and compacted dykes) which do not receive any runoff should therefore be chosen for to hold incubation hapas, and the pond inlets should be turned off during heavy rainfall. Hatchability depression by stagnant water could be forestalled by limiting incubation density to 480 eggs / litre or by partially renewing the incubation water on a daily basis. By so doing, some Cameroon smallholders have successfully engaged in regular on-farm reproduction of Clarias gariepinus

Inhibition of hatchability of African catfish (Clarias gariepinus) eggs on-farm by rainfall, sunshine and water stagnation

To diagnose the impact of rainfall and temperature range on hatchability of Clarias gariepinus eggs incubated in hapas and in outdoor basins, some incubating eggs were protected against the physical impact of raindrops, some were subjected to various turbidity levels, some were protected from direct sunrays and others were incubated at various densities (number of eggs/litre of water) in flowing Vs stagnant water. Data analyses showed that, unaffected by impact of raindrops (P greater than 0.05), hatchability was inversely proportional to both turbidity (coefficient = -0.971), exposure to sunshine (P less than 0.007) and incubation density (coefficient = -0.973). Measures to ensure that on-farm incubation systems are free from turbidity, wide temperature fluctuations and anoxia, were thus highlighted as prerequired for successful incubation of Clarias gariepinus eggs

Popularisation of amphibian tadpoles in nursing African catfish (Clarias gariepinus) fingerlings in hapas

In order to enhance the resistance of Clarias gariepinus fingerlings to the multiple predators of lakes and floodplains, we tested the hypothesis that tadpoles were cheap food supplements for the small-size fingerlings usually produced by hatcheries. Six batches of fingerlings (average weight =10.35 g) were stocked in six hapas and supplied with feed pellets for 56 days. Three of the six batches (experimental triplicate) were additionally supplied with tadpoles caught from surrounding nursery ponds while the other three (control triplicate) received none. Comparison of treatments showed that, consumption of tadpoles conferred significantly higher survivals (P 50g) for growing out, even through re-stocking the many over-exploited lakes and flood plains of Africa.Key words: Fingerlings, catfish, tadpoles, Clarias, re-stockin

Improving on-farm hatchability of Clarias gariepinus eggs by narrowing the range of incubation temperature

In order to facilitate the reproduction of African catfish Clarias gariepinus by smallholders who cannot afford hatchery buildings, electricity and pipe-borne water, the hatchability of fertilised eggs was assessed under the conditions of a dry and a rainy season, as well as under artificial conditions to protect incubating eggs from wide temperature variability. This comprised incubation in small vs. in large water volumes, in covered vs. in exposed vessels, at surface vs. at bottom of vessels and in brightly coloured vs. in black vessels. During the dull rainy days, temperatureranged from 24 to 27°C in hapas (implanted in a 200,000 L pond) and from 24 - 30°C in 30 L plastic tanks, regardless of covering or depth of measurement. During the bright sunny days, water temperature varied from 23 - 30 °C in the hapas and from 19 – 37 °C in the plastic tanks. Covering with white locally available polythene bags, enabled the narrowing of temperature range in tanks but not in hapas (ponds). Tank colour did not significantly affect the water temperature. Temperature ranges were narrower at bottoms than at surfaces in hapas but not in tanks. Egg hatchability was inversely proportional to temperature range: the narrowest range conferred a hatchability of 57.21 % while the widest range completely inhibited it. These results were used as bases for recommending best practices for on-farm incubation of C. gariepinus eggs.Key words: Smallholders, On-farm incubation, improved hatchability

The effect of <i>Artemia</i> -supplementation of dry foods on growth and survival of <i>Clarias gariepinus</i> (Burchell 1822) larvae

Two experiments were performed in order to determine the effect of supplementation of dry foods with live Artemia nauplii on the growth, survival, rate of cannibalism, and length-weight relationships of Clarias gariepinus larvae. It was found that Artemia -supplementation resulted in a significantly higher growth rate. The "condition", expressed as a length-weight relationship, was likewise altered after supplementation. The survival and rate of cannibalism were not influenced by supplementation. Artemia -supplementation of dry foods was compared with other approaches which are based on the concept of the 'adaptation weight'