Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture

Some aspects of complex interactions involving soil mesofauna: analysis of the results from a Scottish woodland

Stepwise regression modelling and canonical correspondence analysis were used to analyse data on soil properties and the abundance of soil mesofauna collected from a woodland typical of the Borders of Scotland. The pattern of relationships revealed by stepwise regression models was different for each month, and the models compiled on the overall dataset were generally weaker than those compiled for separate months. Functional relationships among different microarthropods revealed by stepwise regression modelling are summarised in a structural model of their statistical associations. Interpretation of specific relationships revealed is given and implications for dynamic simulation models are discussed. Canonical correspondence analysis revealed that both microbial feeding nematodes (MF) and plant feeding nematodes (PF) appear to prefer a high level of bacteria and moisture, glomalin and organic matter in the soil. Close scrutiny, however, reveals that microbial feeding nematodes have a particularly high affinity to the sites with a high level of bacteria and organic matter, whilst plant feeding nematodes appear to be more associated with moisture and glomalin. Folsomia candida was abundant in sites with a higher pH level (pH ranged between 3.1 and 4.9), but was not abundant in sites with high ergosterol or a high bacteria, moisture, glomalin and organic matter level. However, other Collembola (mainly represented by Folsomia quadrioculata) appeared to be associated with high levels of ectomycorrhizal fungi. As F. candida is known to feed on fungal food sources, the results suggest that the relatively high local abundances of this collembolan might have caused local declines in ectomycorrhizal fungi, reflected, in turn, in the increase in pH. In addition, environmental plasticity of this species might have allowed them to expand into areas with low fungal density by utilising alternative food sources. The fact that F. candida was a dominant microarthropod in the majority of the samples collected in this research also supports this point. However, for those samples where F. candida were less abundant, overcompensatory fungal growth due to grazing by mites and other Collembola was implicated. Overall, our results suggest that both direct negative and indirect positive effects of the microarthropod community on specific fungal groups appear to take place. The differential effect of specific mesofaunal groups on other soil biota justifies their detailed representation in dynamic simulation models of soil ecosystems

Ciliary IFT88 protects coordinated adolescent growth plate ossification from disruptive physiological mechanical forces

Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule-based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88fl/fl) in the juvenile and adolescent skeleton using a cartilage-specific, inducible Cre (AggrecanCreERT2 Ift88fl/fl). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano-dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces