Biology subjects

Kawaguchi, E.

Publications and source records attributed to Kawaguchi, E..

4 recordsLinked to original sources

bioRxiv2024

Pathway Polygenic Risk Scores (pPRS) for the Analysis of Gene-environment Interaction

A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS x E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will water down the underlying signal in former subset, leading to reduced power to detect PRS x E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS x E interaction can yield substantially greater power than testing overall PRS x E interaction. We also analyze a large study (N=78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS x NSAIDs interaction (p=0.41) is observed, a significant pPRS x NSAIDs interaction (p=0.0003) is identified based on SNPs within the TGF-{beta} / gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5th percentile of the TGF-{beta}/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95th percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective. Author SummaryThe identification of polygenic risk score (PRS) by environment (PRSxE) interactions may provide clues to underlying biology and facilitate targeted disease prevention strategies. The standard approach to computing a PRS likely includes many variants that affect disease without regard to E, reducing power to detect PRS x E interactions. We utilize gene annotation tools to develop pathway-based PRS (pPRS) scores and show by simulation studies that testing pPRS x E interaction can yield substantially greater power than testing PRS x E, while also integrating biological knowledge into the analysis. We apply our method to a large study of colorectal cancer to identify a significant pPRS x NSAIDs interaction (p=0.0003) based on SNPs within the TGF-{beta} / gonadotropin releasing hormone receptor (GRHR) pathway. Our findings suggest that focusing on genetic susceptibility within biologically informed pathways may be more sensitive for identifying exposures that can be considered as part of a precision prevention approach.

genetics↗

bioRxiv2024

Highly efficient XIST reactivation in female hPSC by transient dual inhibition of TP53 and DNA methylation during Cas9 mediated genome editing

Erosion of X-chromosome inactivation (XCI) complicates disease and developmental modeling in female human pluripotent stem cells (hPSCs). Previous studies demonstrated that Cas9-mediated editing of the XIST promoter via non-homologous end joining (NHEJ) or homology-directed repair (HDR) with a selection cassette upstream of XIST can trigger DNA demethylation and XIST reactivation, restoring XCI. Here, we show that NHEJ-mediated XCI reacquisition is more stable during differentiation than HDR. We further developed a novel, efficient XIST reactivation method by combining TP53 inhibition with DNA methylation maintenance suppression during Cas9-mediated NHEJ, offering a robust approach to achieving stable XCI in female hPSCs for diverse applications.

cell biology↗

bioRxiv2019

Evaluation of host effects on ectomycorrhizal fungal community compositions in a forest landscape in northern Japan

Community compositions of ectomycorrhizal (ECM) fungi are similar within the same host taxa. However, careful interpretation is required to determine whether the combination of ECM fungi and plants is explained by the host preference of ECM fungi or by the influence of neighboring conspecific and/or heterospecific hosts. In the present study, we aimed to evaluate the effects of host species on the ECM community compositions in a forest landscape (~ 10 km) where monodominant forest stands of six ECM host species belonging to three families were patchily distributed. The ECM communities were identified with DNA metabarcoding. A total of 180 ECM operational taxonomic units (OTUs) were detected. The ECM community compositions were primarily structured by host species and families, regardless of the soil environments and spatial arrangements of the sampling plots. In addition, 38 ECM OTUs were detected from particular host tree species. Furthermore, the neighboring plots harbored similar fungal compositions, although the host species were different. The relative effect of the spatial factors on the ECM compositions was weaker than that of host species. Our results suggest that the host preference of ECM fungi is a primary determinant of ECM fungal compositions in the forest landscape.

ecology↗

bioRxiv2019

Biogeographic patterns of ectomycorrhizal fungal communities associated with Castanopsis sieboldii across the Japanese archipelago

Biogeographic patterns in ectomycorrhizal (ECM) fungal communities and their drivers have been elucidated, including effects of host tree species and abiotic (climatic and edaphic) conditions. At these geographic scales, genotypic diversity and composition of single host tree species change with spatial and environmental gradients, reflecting their historical dispersal events. However, whether the host genotypes can be associated with the biogeographic patterns of ECM communities remains unclear. We investigated the biogeographic pattern of ECM fungal community associated with the single host species Castanopsis sieboldii (Fagaceae), whose genotypic diversity and composition across the Japanese archipelago has already been evaluated, and we quantified the effect of host genotypes on the biogeographic pattern. Richness and community composition of ECM fungi changed with latitude and longitude; these biogeographic changes of ECM community were significantly explained by host genotypic variables. Quantitative analyses showed a higher relative explanatory power of climatic and spatial variables than that of host genotypic variables for the biogeographic patterns in the ECM community. Our results suggest the importance of historical events of host dispersal in determining the biogeographic patterns of the ECM fungal community, while their explanation power was lower than that for climatic filtering and/or fungal dispersal.

ecology↗