Bayesian network analysis incorporating genetic anchors complements conventional Mendelian randomization approaches for exploratory analysis of causal relationships in complex data

Mendelian randomization (MR) implemented through instrumental variables analysis is an increasingly popular causal inference tool used in genetic epidemiology. But it can have limitations for evaluating simultaneous causal relationships in complex data sets that include, for example, multiple genetic predictors and multiple potential risk factors associated with the same genetic variant. Here we use real and simulated data to investigate Bayesian network analysis (BN) with the incorporation of directed arcs, representing genetic anchors, as an alternative approach. A Bayesian network describes the conditional dependencies/independencies of variables using a graphical model (a directed acyclic graph) with an accompanying joint probability. In real data, we found BN could be used to infer simultaneous causal relationships that confirmed the individual causal relationships suggested by bi-directional MR, while allowing for the existence of potential horizontal pleiotropy (that would violate MR assumptions). In simulated data, BN with two directional anchors (mimicking genetic instruments) had greater power for a fixed type 1 error than bi-directional MR, while BN with a single directional anchor performed better than or as well as bi-directional MR. Both BN and MR could be adversely affected by violations of their underlying assumptions (such as genetic confounding due to unmeasured horizontal pleiotropy). BN with no directional anchor generated inference that was no better than by chance, emphasizing the importance of directional anchors in BN (as in MR). Under highly pleiotropic simulated scenarios, BN outperformed both MR (and its recent extensions) and two recently-proposed alternative approaches: a multi-SNP mediation intersection-union test (SMUT) and a latent causal variable (LCV) test. We conclude that BN incorporating genetic anchors is a useful complementary method to conventional MR for exploring causal relationships in complex data sets such as those generated from modern "omics" technologies

Going global: The introduction of the Asian isopod Ianiropsis serricaudis Gurjanova (Crustacea: Peracarida) to North America and Europe

The Asian isopod Ianiropsis serricaudis is now well established in fouling communities, often associated with introduced ascidians, throughout the Northern Hemisphere but has gone largely unnoticed because of its diminutive size (typically less than 3 mm in length) and the difficulties of identifying small peracarid crustaceans. Known locations include the northeastern Pacific (Puget Sound, San Francisco Bay, and Monterey Bay), the northwestern Atlantic (from the Gulf of Maine to Barnegat Bay, NJ), and the northeastern Atlantic (England and the Netherlands). We predict that this species is widespread along North America and European coasts, and may already be introduced to cold temperate waters of the Southern Hemisphere as well

Chromosome 11q13.5 variant associated with childhood eczema:an effect supplementary to filaggrin mutations

BackgroundAtopic eczema is a common inflammatory skin disease with multifactorial etiology. The genetic basis is incompletely understood; however, loss of function mutations in the filaggrin gene (FLG) are the most significant and widely replicated genetic risk factor reported to date. The first genome-wide association study in atopic eczema recently identified 2 novel genetic variants in association with eczema susceptibility: a single nucleotide polymorphism on chromosome 11q13.5 (rs7927894) and a single nucleotide polymorphism (rs877776) within the gene encoding hornerin on chromosome 1q21.ObjectiveTo test the association of these 2 novel variants with pediatric eczema and to investigate their interaction with FLG null mutations.MethodsCase-control study to investigate the association of rs7927894, rs877776 and the 4 most prevalent FLG null mutations with moderate-severe eczema in 511 Irish pediatric cases and 1000 Irish controls. Comprehensive testing for interaction between each of the loci was also performed.ResultsThe association between rs7927894 and atopic eczema was replicated in this population (P = .0025, χ2 test; odds ratio, 1.27; 95% CI, 1.09-1.49). The 4 most common FLG null variants were strongly associated with atopic eczema (P = 1.26 × 10−50; combined odds ratio, 5.81; 95% CI, 4.51-7.49). Interestingly, the rs7927894 association was independent of the well-established FLG risk alleles and may be multiplicative in its effect. There was no significant association between rs877776 and pediatric eczema in this study.ConclusionSingle nucleotide polymorphism rs7927894 appears to mark a genuine eczema susceptibility locus that will require further elucidation through fine mapping and functional analysis

IGFBP-1 in Cardiometabolic Pathophysiology—Insights From Loss-of-Function and Gain-of-Function Studies in Male Mice

We have previously reported that overexpression of human insulin-like growth factor binding protein (IGFBP)-1 in mice leads to vascular insulin sensitization, increased nitric oxide bioavailability, reduced atherosclerosis, and enhanced vascular repair, and in the setting of obesity improves glucose tolerance. Human studies suggest that low levels of IGFBP-1 are permissive for the development of diabetes and cardiovascular disease. Here we seek to determine whether loss of IGFBP-1 plays a causal role in the predisposition to cardiometabolic disease. Metabolic phenotyping was performed in transgenic mice with homozygous knockout of IGFBP-1. This included glucose, insulin, and insulin-like growth factor I tolerance testing under normal diet and high-fat feeding conditions. Vascular phenotyping was then performed in the same mice using vasomotor aortic ring studies, flow cytometry, vascular wire injury, and angiogenesis assays. These were complemented with vascular phenotyping of IGFBP-1 overexpressing mice. Metabolic phenotype was similar in IGFBP-1 knockout and wild-type mice subjected to obesity. Deletion of IGFBP-1 inhibited endothelial regeneration following injury, suggesting that IGFBP-1 is required for effective vascular repair. Developmental angiogenesis was unaltered by deletion or overexpression of IGFBP-1. Recovery of perfusion following hind limb ischemia was unchanged in mice lacking or overexpressing IGFBP-1; however, overexpression of IGFBP-1 stimulated hindlimb perfusion and angiogenesis in insulin-resistant mice. These findings provide new insights into the role of IGFBP-1 in metabolic and vascular pathophysiology. Irrespective of whether loss of IGFBP-1 plays a causal role in the development of cardiometabolic disorders, increasing IGFBP-1 levels appears effective in promoting neovascularization in response to ischemia

Restoring native forest understory: The influence of ferns and light in a hawaiian experiment

Ecological restoration is an increasingly important component of sustainable land management. We explore potential facilitative relationships for enhancing the cost-effectiveness of restoring native forest understory, focusing on two factors: (1) overstory shade and (2) possible facilitation by a fern (Dryopteris wallichiana), one of few native colonists of pasture in our montane Hawai\u27i study system. We planted 720 understory tree seedlings and over 4000 seeds of six species under six planting treatments: a full factorial combination of low, medium and high light, situating plantings in either the presence or absence of a mature fern. After three years, 75% of outplanted seedlings survived. Seedling survivorship was significantly higher in the presence of a fern (79% vs. 71% without a fern) and in medium and low light conditions (81% vs. 64% in high light). Relative height was highest at low to medium light levels. After 2.2 years, 2.8% of the planted seeds germinated. We observed no significant differences in seed germination relative to light level or fern presence. Analyzing several approaches, we found nursery germination of seeds followed by outplanting ca. 20% less costly than direct seeding in the field. This study opens new questions about facilitation mechanisms that have the potential to increase the extent and effectiveness of restoration efforts. © 2013 by the authors

Going global: The introduction of the Asian isopod Ianiropsis serricaudis Gurjanova (Crustacea: Peracarida) to North America and Europe

The Asian isopod Ianiropsis serricaudis is now well established in fouling communities, often associated with introduced ascidians, throughout the Northern Hemisphere but has gone largely unnoticed because of its diminutive size (typically less than 3 mm in length) and the difficulties of identifying small peracarid crustaceans. Known locations include the northeastern Pacific (Puget Sound, San Francisco Bay, and Monterey Bay), the northwestern Atlantic (from the Gulf of Maine to Barnegat Bay, NJ), and the northeastern Atlantic (England and the Netherlands). We predict that this species is widespread along North America and European coasts, and may already be introduced to cold temperate waters of the Southern Hemisphere as well