Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Could occupational physical activity mitigate the link between moderate kidney dysfunction and coronary heart disease?

Background

Chronic kidney disease is now regarded as a risk factor for cardiovascular disease. The impact of occupational or non-occupational physical activity (PA) on moderate decreases of renal function is uncertain.

We aimed to identify the potential association of PA (occupational and leisure-time) on early decline of estimated glomerular filtration rate (eGFR) and to determine the potential mediating effect of PA on the relationship between eGFR and heart disease.

From the PRIME study analyses were conducted in 1058 employed men. Energy expended during leisure, work and commuting was calculated. Linear regression analyses were used to determine the link between types of PA and moderate decrements of eGFR determined with the KDIGO guideline at the baseline assessment. Cox proportional hazards analyses were used to explore the potential effect of PA on the relationship between eGFR and heart disease, ascertained during follow-up over 10 years.

For these employed men, and after adjustment for known confounders of GFR change, more time spent sitting at work was associated with increased risk of moderate decline in kidney function, while carrying objects or being active at work was associated with decreased risk. In contrast, no significant link with leisure PA was apparent. No potential mediating effect of occupational PA was found for the relationship between eGFR and coronary heart disease.

Occupational PA (potential modifiable factors) could provide a dual role on early impairment of renal function, without influence on the relationship between early decrease of e-GFR and CHD risk.

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

Exact and heuristic methods for solving Boolean games

Boolean games are a framework for reasoning about the rational behavior of agents whose goals are formalized using propositional formulas. Compared to normal form games, a well-studied and related game framework, Boolean games allow for an intuitive and more compact representation of the agents’ goals. So far, Boolean games have been mainly studied in the literature from the Knowledge Representation perspective, and less attention has been paid on the algorithmic issues underlying the computation of solution concepts. Although some suggestions for solving specific classes of Boolean games have been made in the literature, there is currently no work available on the practical performance. In this paper, we propose the first technique to solve general Boolean games that does not require an exponential translation to normal-form games. Our method is based on disjunctive answer set programming and computes solutions (equilibria) of arbitrary Boolean games. It can be applied to a wide variety of solution concepts, and can naturally deal with extensions of Boolean games such as constraints and costs. We present detailed experimental results in which we compare the proposed method against a number of existing methods for solving specific classes of Boolean games, as well as adaptations of methods that were initially designed for normal-form games. We found that the heuristic methods that do not require all payoff matrix entries performed well for smaller Boolean games, while our ASP based technique is faster when the problem instances have a higher number of agents or action variables.

Semantics for possibilistic answer set programs: uncertain rules versus rules with uncertain conclusions

Although Answer Set Programming (ASP) is a powerful framework for declarative problem solving, it cannot in an intuitive way handle situations in which some rules are uncertain, or in which it is more important to satisfy some constraints than others. Possibilistic ASP (PASP) is a natural extension of ASP in which certainty weights are associated with each rule. In this paper we contrast two different views on interpreting the weights attached to rules. Under the first view, weights reflect the certainty with which we can conclude the head of a rule when its body is satisfied. Under the second view, weights reflect the certainty that a given rule restricts the considered epistemic states of an agent in a valid way, i.e. it is the certainty that the rule itself is correct. The first view gives rise to a set of weighted answer sets, whereas the second view gives rise to a weighted set of classical answer sets.

Characterizing and Extending Answer Set Semantics using Possibility Theory

Answer Set Programming (ASP) is a popular framework for modelling combinatorial problems. However, ASP cannot be used easily for reasoning about uncertain information. Possibilistic ASP (PASP) is an extension of ASP that combines possibilistic logic and ASP. In PASP a weight is associated with each rule, whereas this weight is interpreted as the certainty with which the conclusion can be established when the body is known to hold. As such, it allows us to model and reason about uncertain information in an intuitive way. In this paper we present new semantics for PASP in which rules are interpreted as constraints on possibility distributions. Special models of these constraints are then identified as possibilistic answer sets. In addition, since ASP is a special case of PASP in which all the rules are entirely certain, we obtain a new characterization of ASP in terms of constraints on possibility distributions. This allows us to uncover a new form of disjunction, called weak disjunction, that has not been previously considered in the literature. In addition to introducing and motivating the semantics of weak disjunction, we also pinpoint its computational complexity. In particular, while the complexity of most reasoning tasks coincides with standard disjunctive ASP, we find that brave reasoning for programs with weak disjunctions is easier.

Using Answer Set Programming for Solving Boolean Games

Boolean games are a framework for reasoning about the rational behaviour of agents, whose goals are formalized using propositional formulas. They offer an attractive alternative to normal-form games, because they allow for a more intuitive and more compact encoding. Unfortunately, however, there is currently no general, tailor-made method available to compute the equilibria of Boolean games. In this paper, we introduce a method for finding the pure Nash equilibria based on disjunctive answer set programming. Our method is furthermore capable of finding the core elements and the Pareto optimal equilibria, and can easily be modified to support other forms of optimality, thanks to the declarative nature of disjunctive answer set programming. Experimental results clearly demonstrate the effectiveness of the proposed method.

Decentralized Computation of Pareto Optimal Pure Nash Equilibria of Boolean Games with Privacy Concerns

In Boolean games, agents try to reach a goal formulated as a Boolean formula. These games are attractive because of their compact representations. However, few methods are available to compute the solutions and they are either limited or do not take privacy or communication concerns into account. In this paper we propose the use of an algorithm related to reinforcement learning to address this problem. Our method is decentralized in the sense that agents try to achieve their goals without knowledge of the other agents’ goals. We prove that this is a sound method to compute a Pareto optimal pure Nash equilibrium for an interesting class of Boolean games. Experimental results are used to investigate the performance of the algorithm.