| 1. |
- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- 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 genomewide 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 agedependency 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.
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| 2. |
- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- 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/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 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.
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| 3. |
- Breitfeld, Jana, et al.
(författare)
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Genetic dissection of serum vaspin highlights its causal role in lipid metabolism
- 2023
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Ingår i: Obesity. - 1930-7381. ; 31:11, s. 2862-2874
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10−8, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.
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| 4. |
- Dharamshi, Jennah, et al.
(författare)
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Gene gain facilitated endosymbiotic evolution of Chlamydiae
- 2023
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Ingår i: Nature Microbiology. - : Springer Nature. - 2058-5276. ; 8, s. 40-54
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Tidskriftsartikel (refereegranskat)abstract
- Chlamydiae is a bacterial phylum composed of obligate animal and protist endosymbionts. However, other members of the Planctomycetes-Verrucomicrobia-Chlamydiae superphylum are primarily free living. How Chlamydiae transitioned to an endosymbiotic lifestyle is still largely unresolved. Here we reconstructed Planctomycetes-Verrucomicrobia-Chlamydiae species relationships and modelled superphylum genome evolution. Gene content reconstruction from 11,996 gene families suggests a motile and facultatively anaerobic last common Chlamydiae ancestor that had already gained characteristic endosymbiont genes. Counter to expectations for genome streamlining in strict endosymbionts, we detected substantial gene gain within Chlamydiae. We found that divergence in energy metabolism and aerobiosis observed in extant lineages emerged later during chlamydial evolution. In particular, metabolic and aerobic genes characteristic of the more metabolically versatile protist-infecting chlamydiae were gained, such as respiratory chain complexes. Our results show that metabolic complexity can increase during endosymbiont evolution, adding an additional perspective for understanding symbiont evolutionary trajectories across the tree of life.
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| 5. |
- García-Montaner, Andrea, 1988-
(författare)
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Genome evolution of a bee-associated bacterium
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The use of large-scale comparative genomics allows us to explore the genetic diversity and mechanisms of evolution of related organisms. This thesis has focused on the application of such approaches to study Lactobacillus kunkeei, a bacterial inhabitant of the honeybee gut.We produced 102 novel complete genomes from L. kunkeei, which were used in four large comparative studies. In the first study, 41 bacterial strains were isolated from the crop of honeybees whose populations were geographically isolated. Their genome sequences revealed differences in gene contents, including the mobilome, which were mostly phylogroup-specific. However, differences in strain diversity and co-occurrence between both locations were observed. In the second study, we obtained 61 bacterial isolates from neighboring hives at different timepoints during the summer. We observed that strain diversity seemed hive-specific and relatively constant in time. Surprisingly, the observed mobilome also showed hive specificity and was maintained through the summer.The novel genome data were combined with previously published genomes, allowing us to perform deep comparative analyses on the evolution of the species using a total of 126 genomes. We determined that, despite the large number of sequenced genomes, L. kunkeei has an open pangenome. Besides, we evaluated the effects of recombination on the species core genome, and concluded that it mainly evolves through mutation events.In the last study we described the mechanisms of evolution of a cluster of 5 giant genes (about 90 kb long in total) that are unique to L. kunkeei and the closest sister species. Their patterns of evolution do not reflect those of the species core genome. We concluded that they originated by duplication events, and have diverged by accumulation of both mutations and recombination events. We predicted a potential interaction between the proteins encoded by two of them, and we hypothesized a role in host-specific interaction for another protein.In conclusion, these studies have provided novel and cohesive knowledge on the composition and dynamics of different populations of L. kunkeei, and may have contributed to better understand its ecological niche.
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| 6. |
- Halter, Tamara, et al.
(författare)
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Ecology and evolution of chlamydial symbionts of arthropods
- 2022
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Ingår i: ISME Communications. - : Springer Nature. - 2730-6151. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- The phylum Chlamydiae consists of obligate intracellular bacteria including major human pathogens and diverse environmental representatives. Here we investigated the Rhabdochlamydiaceae, which is predicted to be the largest and most diverse chlamydial family, with the few described members known to infect arthropod hosts. Using published 16 S rRNA gene sequence data we identified at least 388 genus-level lineages containing about 14 051 putative species within this family. We show that rhabdochlamydiae are mainly found in freshwater and soil environments, suggesting the existence of diverse, yet unknown hosts. Next, we used a comprehensive genome dataset including metagenome assembled genomes classified as members of the family Rhabdochlamydiaceae, and we added novel complete genome sequences of Rhabdochlamydia porcellionis infecting the woodlouse Porcellio scaber, and of 'Candidatus R. oedothoracis' associated with the linyphiid dwarf spider Oedothorax gibbosus. Comparative analysis of basic genome features and gene content with reference genomes of well-studied chlamydial families with known host ranges, namely Parachlamydiaceae (protist hosts) and Chlamydiaceae (human and other vertebrate hosts) suggested distinct niches for members of the Rhabdochlamydiaceae. We propose that members of the family represent intermediate stages of adaptation of chlamydiae from protists to vertebrate hosts. Within the genus Rhabdochlamydia, pronounced genome size reduction could be observed (1.49-1.93 Mb). The abundance and genomic distribution of transposases suggests transposable element expansion and subsequent gene inactivation as a mechanism of genome streamlining during adaptation to new hosts. This type of genome reduction has never been described before for any member of the phylum Chlamydiae. This study provides new insights into the molecular ecology, genomic diversity, and evolution of representatives of one of the most divergent chlamydial families.
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| 7. |
- Holgersson, Johan, et al.
(författare)
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Hypothermic versus Normothermic Temperature Control after Cardiac Arrest
- 2022
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Ingår i: NEJM Evidence. - 2766-5526. ; 1:11, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDThe evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics.METHODSAn individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence).RESULTSThe primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups.CONCLUSIONSHypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)
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| 8. |
- Horn, Matthias, et al.
(författare)
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A*-based construction of decision diagrams for a prize-collecting scheduling problem
- 2021
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Ingår i: Computers & Operations Research. - : Elsevier. - 0305-0548 .- 1873-765X. ; 126
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Tidskriftsartikel (refereegranskat)abstract
- Decision diagrams (DDs) have proven to be useful tools in combinatorial optimization. Relaxed DDs represent discrete relaxations of problems, can encode essential structural information in a compact form, and may yield strong dual bounds. We propose a novel construction scheme for relaxed multi-valued DDs for a scheduling problem in which a subset of elements has to be selected from a ground set and the selected elements need to be sequenced. The proposed construction scheme builds upon A search guided by a fast-to-calculate problem-specific dual bound heuristic. In contrast to traditional DD compilation methods, the new approach does not rely on a correspondence of DD layers to decision variables. For the considered kind of problem, this implies that multiple nodes representing the same state at different layers can be avoided, and consequently also many redundant isomorphic substructures. For keeping the relaxed DD compact, a new mechanism for merging nodes in a layer-independent way is suggested. For our prize-collecting job sequencing problem, experimental results show that the DDs from our A -based approach provide substantially better bounds while frequently being an order-ofmagnitude smaller than DDs obtained from traditional compilation methods, given about the same time. To obtain a heuristic solution and a corresponding lower bound, we further propose to construct a restricted DD based on the relaxed one, thereby substantially exploiting already gained information. This approach outperforms a standalone restricted DD construction, basic constraint programming and mixed integer linear programming approaches, and a variable neighborhood search in terms of solution quality on most of our benchmark instances.
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| 9. |
- Horn, Matthias, et al.
(författare)
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A* Search for Prize-Collecting Job Sequencing with One Common and Multiple Secondary Resources
- 2021
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Ingår i: Annals of Operations Research. - : SPRINGER. - 0254-5330 .- 1572-9338. ; 302, s. 477-505
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Tidskriftsartikel (refereegranskat)abstract
- We consider a sequencing problem with time windows, in which a subset of a given set of jobs shall be scheduled. A scheduled job has to execute without preemption and during this time, the job needs both a common resource for a part of the execution as well as a secondary resource for the whole execution time. The common resource is shared by all jobs while a secondary resource is shared only by a subset of the jobs. Each job has one or more time windows and due to these, it is not possible to schedule all jobs. Instead, each job is associated with a prize and the task is to select a subset of jobs which yields a feasible schedule with a maximum sum of prizes. First, we argue that the problem is NP-hard. Then, we present an exact A* algorithm and derive different upper bounds for the total prize; these bounds are based on constraint and Lagrangian relaxations of a linear programming relaxation of a multidimensional knapsack problem. For comparison, a compact mixed integer programming (MIP) model and a constraint programming model are also presented. An extensive experimental evaluation on three types of problem instances shows that the A* algorithm outperforms the other approaches and is able to solve small to medium size instances with up to about 40 jobs to proven optimality. In cases where A* does not prove that an optimal solution is found, the obtained upper bounds are stronger than those of the MIP model.
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