The carbohydrate-linked phosphorylcholine of the parasitic nematode product ES-62 modulates complement activation

Parasitic nematodes manufacture various carbohydratelinked phosphorylcholine (PCh)-containing molecules, including ES-62, a protein with an N-linked glycan terminally substituted with PCh. The PCh component is biologically important because it is required for immunomodulatory effects. We showed that most ES-62 was bound to a single protein, C-reactive protein (CRP), in normal human serum, displaying a calcium-dependent, high-avidity interaction and ability to form large complexes. Unexpectedly, CRP binding to ES-62 failed to efficiently activate complement as far as the C3 convertase stage in comparison with PCh-BSA and PCh-containing Streptococcus pneumoniae cell wall polysaccharide. C1q capture assays demonstrated an ES-62-CRP-C1q interaction in serum. The three ligands all activated C1 and generated C4b to similar extents. However, a C2a active site was not generated following ES-62 binding to CRP, demonstrating that C2 cleavage was far less efficient for ES-62-containing complexes. We proposed that failure of C2 cleavage was due to the flexible nature of carbohydrate-bound PCh and that reduced proximity of the C1 complex was the reason that C2 was poorly cleaved. This was confirmed using synthetic analogues that were similar to ES-62 only in respect of having a flexible PCh. Furthermore, ES-62 was shown to deplete early complement components, such as the rate-limiting C4, following CRP interaction and thereby inhibit classical pathway activation. Thus, flexible PCh-glycan represents a novel mechanism for subversion of complement activation. These data illustrate the importance of the rate-limiting C4/C2 stage of complement activation and reveal a new addition to the repertoire of ES-62 immunomodulatory mechanisms with possible therapeutic applications

A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data. Conclusions: Our study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD

Rediscovering nature in everyday settings : or how to create healthy environments and healthy people

It is estimated that half of the world&rsquo;s population now live in urban environments. Urban living necessitates a removal from nature, yet evidence indicates that contact with nature is beneficial for human health. In fact, everyday urban places, such as where people live, study, and work, provide opportunities to bring nature back into cities to contribute to positive, healthy environments for people and to foster the human&ndash;nature connection. The inclusion of more nature in cities could have additional environmental benefits, such as habitat provision and improving the environmental performance of built environments. In the context of climate change, outcomes such as these assume further importance. This article explores how common urban places can foster links between people and nature, and generate positive health and well-being outcomes. We achieve this by exploring nature in the everyday settings of schools and residential housing. <br /

Common disorders are quantitative traits

After drifting apart for 100 years, the two worlds of genetics - quantitative genetics and molecular genetics - are finally coming together in genome-wide association (GWA) research, which shows that the heritability of complex traits and common disorders is due to multiple genes of small effect size. We highlight a polygenic framework, supported by recent GWA research, in which qualitative disorders can be interpreted simply as being the extremes of quantitative dimensions. Research that focuses on quantitative traits - including the low and high ends of normal distributions - could have far-reaching implications for the diagnosis, treatment and prevention of the problematic extremes of these traits