Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 937 records · Page 52Linked to original sources

bioRxiv2020

Dietary supplementation with products of Citrus reticulata "Chachi" for improving the fecal microbiome of weaned piglets

Nutritional interventions play a critical role in modifying the intestinal microbiome of host animals. This study was conducted to interrogate the physiological effects on fecal microflora of weaned piglets via the dietary supplemented with two types of products of Citrus reticulata "Chachi", respectively. For this purpose, A total of 72 piglets with uniform sizes were randomly assigned to four dietary treatment groups consisted of a negative control group (NCG), a fermented citrus reticulata "Chachi" pulp group (FCRPG), a Citri Reticulatae Pericarpium group (CRPG) and a positive control group (PCG) in a 21-day feeding trial. After the raising experiment, fresh feces of piglets were analyzed systematically using multi-omics technologies. Metagenomics method with high-throughput compositional characterization indicated that the architecture and diversity of fecal microbiome were both influenced by these two additives and compound antibiotics. Metabolite analysis showed that FCRPG have an significant effects on fecal short-chain fatty acids (SCFAs) among four treatment groups. Results of functional proteomics approaches found that FCRPG presented the highest butyrate metabolic level, and CRPG showed the highest flavone and flavonol biosynthesis level in feces. In addition, NCP produced an effective effect on adjusting fecal microbiota profile. Consequently, our findings demonstrate that dietary supplementation with FCRP or CRP modulates the microbial taxa, metabolic and proteomic alterations in fecal microbiota of weaned piglets for health maintaining.

microbiology↗

bioRxiv2020

Evolution in Sinocyclocheilus cavefish is marked by rate shifts, reversals and origin of novel traits

Epitomized by the well-studied Astyanax mexicanus, cavefishes provide important model organisms to understand adaptations in response to divergent natural selection. However, the spectacular Sinocyclocheilus diversification of China, the most diverse cavefish clade in the world harboring nearly 75 species, demonstrate evolutionary convergence for many traits, yet remain poorly understood in terms of their morphological evolution. Here, using a broad sample of 49 species representative of this diversification, we analyze patterns of Sinocylocheilus evolution in a phylogenetic context. We categorized species into morphs based on eye-related condition: Blind, Micro-eyed (small-eyed), and Normal-eyed and we also considered three habitat types (Troglodytic - cave-restricted; Troglophilic - cave-associated; Surface - outside of caves). Geometric morphometric analyses show Normal-eyed morphs with fusiform shapes being segregated from Blind/Micro-eyed (Eye-regressed) morphs with deeper bodies along the first principal component ("PC") axis. The second PC axis accounts for shape complexity related to the presence of horns. Ancestral character reconstructions of morphs suggest at least three independent origins of Blind morphs, each with different levels of modification in relation to the typical morphology of ancestral Normal-eyed morphs. Interestingly, only some Blind or Micro-eyed morphs bear horns and they are restricted to a single clade (Clade B) and arising from a Troglodytic ancestral species. Our geophylogeny shows an east-to-west diversification spanning the Pliocene and the Pleistocene, with Troglodytic species dominating karstic subterranean habitats of the plains whereas predominantly Surface species inhabit streams and pools in hills to the west (perhaps due to the scarcity of caves). Integration of morphology, phylogeny and geography suggests Sinocyclocheilus are pre-adapted for cave dwelling. Analyses of evolutionary rates suggest that lineages leading to Blind morphs were characterized by significant rate shifts, such as a slowdown in body size evolution and a 3.3 to 12.5 fold increase in the evolutionary rate of eye regression. Furthermore, body size and eye size have undergone reversals, but horns have not, a trait that seem to require substantial evolutionary time to form. These results, compared to the Astyanax model system, indicate Sinocyclocheilus fishes demonstrate extraordinary morphological diversity and variation, offering an invaluable model system to explore evolutionary novelty.

evolutionary biology↗

bioRxiv2020

Comparison of SARS-CoV-2 infections among 3 species of non-human primates

COVID-19, caused by SARS-CoV-2 infection, has recently been announced as a pandemic all over the world. Plenty of diagnostic, preventive and therapeutic knowledges have been enriched from clinical studies since December 2019. However, animal models, particularly non-human primate models, are urgently needed for critical questions that could not be answered in clinical patients, evaluations of anti-viral drugs and vaccines. In this study, two families of non-human primates, Old world monkeys (12 Macaca mulatta, 6 Macaca fascicularis) and New world monkeys (6 Callithrix jacchus), were experimentally inoculated with SARS-CoV-2. Clinical signs were recorded. Samples were collected for analysis of viral shedding, viremia and histopathological examination. Increased body temperature was observed in 100% (12/12) M. mulatta, 33.3% (2/6) M. fascicularis and none (0/6) of C. jacchus post inoculation of SARS-CoV-2. All of M. mulatta and M. fascicularis showed chest radiographic abnormality. Viral genomes were detected in nasal swabs, throat swabs, anal swabs and blood from all 3 species of monkeys. Viral shedding from upper respiratory samples reached the peak between day 6 and day 8 post inoculation. From necropsied M. mulatta and M. fascicularis, the tissues showing virus positive were mainly lung, weasand, bronchus and spleen. No viral genome was seen in any of tissues from 2 necropsied C. jacchus. Severe gross lesions and histopathological changes were observed in lung, heart and stomach of SARS-CoV-2 infected animals. In summary, we have established a NHP model for COVID-19, which could be used to evaluate drugs and vaccines, and investigate viral pathogenesis. M. mulatta is the most susceptible to SARS-CoV-2 infection, followed by M. fascicularis and C. jacchus. One Sentence SummaryM. mulatta is the most susceptible to SARS-CoV-2 infection as compared to M. fascicularis and C. jacchus.

microbiology↗

bioRxiv2020

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity that may underly population disparities in this disease

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underly the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertook a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture were identified. Nine disease loci showed clear ancestral group heterogeneity and implicated antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores performed significantly better when trained on matched ancestral data sets. These analyses help to reveal the genetic bases for disparities in SLE among ancestral groups.

genetics↗

bioRxiv2020

Comparative secretome of Magnaporthe oryzae identified proteins involved in virulence and cell wall integrity

Plant fungal pathogens secrete numerous proteins into the apoplast at the plant-fungus contact sites to facilitate colonization. Only a few secreted proteins were functionally characterized in Magnaporthe oryzae, the fungal pathogen causing rice blast disease worldwide. ALG3 is an -1, 3-mannosyltransferase function in N-glycan synthesis for secreted N-glycosylated proteins, and the {Delta}alg3 mutants show strong defects in cell wall integrity and fungal virulence, indicating a potential effect on the secretion of multiple proteins. In this study, we compared the secretome of wild type and {Delta}alg3 mutants, and identified 51 proteins that require ALG3 for proper secretion. These are predicted to be involved in metabolic processes, interspecies interactions, cell wall organization, and response to chemicals. The tested secreted proteins localized at the apoplast region surrounding the fungal infection hyphae. Moreover, the N-glycosylation of candidate proteins was significantly changed in the {Delta}alg3 mutant, leading to the reduction of protein secretion and abnormal protein localization. Furthermore, we tested the function of two genes, one is a previously reported M. oryzae gene Invertase 1 (INV1) encoding a secreted invertase, and the other one is a gene encoding an Acid mammalian chinitase (AMCase). The fungal virulence was significantly reduced and the cell wall integrity was altered in the {Delta}inv1 and {Delta}amcase mutant strains. Elucidation of the comparative secretome of M. oryzae improves our understanding of the proteins that require ALG3 for secretion, and of their function in fungal virulence and cell wall integrity.

plant biology↗

bioRxiv2020

Introduction of the Aspergillus fumigatus α-1,2-mannosidase MsdS into Trichoderma reesei leads to abnormal polarity and improves the ligno-cellulose degradation

-1,2-Mannosidase is an important enzyme essential for N-glycan processing and plays a significant role in the biosynthesis and organization of fungal cell wall. Lacking of -1,2-mannosidase leads to cell wall defect in yeast and filamentous fungi. Trichoderma reesei is known to be non-toxic to human, and its N-glycan on secreted glycoprotein is Man8GlcNAc2. To evaluate the significance of the N-glycan processing in T. reesei, in this study Aspergillus fumigatus -1, 2-mannosidase MsdS, an enzyme that cleaves N-linked Man8GlcNAc2 in Golgi to produce Man6GlcNAc2 on secreted glycoprotein, was introduced into T. reesei. The msdS-expressing strain Tr-MsdS produced a major glycoform of Man6GlcNAc2 on its secreted glycoproteins, instead of Man8GlcNAc2 in the parent strain. Although the cell wall content of msdS-expressing strain Tr-MsdS was changed, it appeared that the cell wall integrity was not affected. However, phenotypes such as increased conidiation, multiple budding and random branching were observed in strain Tr-MsdS. In addition, expression of MsdS into T. ressei also affected protein secretion and improved the ligno-cellulose degradation of T. reesei. Our results indicate that processing of the N-glycan is species-specific and plays an important role in protein secretion in T. reesei, specially cellulases. Also, our results provide a new strategy to improve cellulases production by interfering the N-glycan processing in T. reesei. ImportanceFor the first time, the N-glycan processing is shown to play an important role in polarized growth and protein secretion in T. reesei. In addition, our results show that alterated N-glycan processing enhances cellulose degradation, which provides a strategy to improve cellulases production in T. reesei.

bioengineering↗

bioRxiv2020

Single-cell RNA sequencing deconvolutes the in vivo heterogeneity of human bone marrow-derived mesenchymal stem cells

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stromal cells, which have a critical role in the maintenance of skeletal tissues such as bone, cartilage, and the fat found in bone marrow. In addition to providing microenvironmental support for hematopoietic processes, BM-MSCs can differentiate into various mesodermal lineages including osteoblast/osteocyte, chondrocyte, and adipocyte cells that are crucial for bone metabolism. While BM-MSCs have high cell-to-cell heterogeneity in gene expression, the cell subtypes that contribute to this heterogeneity in vivo in humans have not been characterized. To investigate the transcriptional diversity of BM-MSCs, we applied single-cell RNA sequencing (scRNA-seq) on freshly isolated CD271+ BM-derived mononuclear cells (BM-MNCs) from two human subjects. We successfully identified LEPRhiCD45low BM-MSCs within the CD271+ BM-MNC population, and further codified the BM-MSCs into distinct subpopulations corresponding to the osteogenic, chondrogenic, and adipogenic differentiation trajectories, as well as terminal-stage quiescent cells. Biological functional annotations of transcriptomes suggest that osteoblast precursors may induce angiogenesis coupled with osteogenesis, and chondrocyte precursors may have the potential to differentiate into myocytes. We discovered transcripts for several cluster of differentiation (CD) markers that were highly expressed (e.g., CD167b, CD91, CD130 and CD118) or absent (e.g., CD74, CD217, CD148 and CD68) in BM-MSCs and could be novel markers for human BM-MSC purification. This study is the first systematic in vivo dissection of human BM-MSCs cell subtypes at the single-cell resolution, revealing insight into the extent of their cellular heterogeneity and bone homeostasis.

cell biology↗

bioRxiv2020

KMT2D Links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-{beta} to the activin A pathway. We found that TGF-{beta} upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D. These findings reveal a tumor-suppressive role of KMT2D and identify miR-147b and activin A as novel therapeutic targets in pancreatic cancer.

cancer biology↗

bioRxiv2020

Transcriptome Analysis in Yeast Reveals the Externality of Position Effect

When a gene is integrated into the chromosome, its activity depends on the genomic context. Although this phenomenon of "position effect" was widely reported, how the integration event affects the local environment, or the "externality" of position effect, remained largely unexplored, let alone the mechanism or phenotypic consequence of such externality. Here, we examined the transcriptome profiles of [~]250 Saccharomyces cerevisiae strains, each with GFP inserted into a different locus of the wild-type strain. We found that the GFP expression level and the change of expression of genes near the integration site decreases in genomic regions with high density of essential genes. This observation was found associated with H3K4me2 by further joint-analysis with public genome-wide histone modification profiles. More importantly, we found that the expression changes of neighboring genes, but not the GFP expression, exerted a significant impact on cellular growth rate. As a result, genomic loci that grant higher GFP expression immediately after the integration will have lower total yield of GFP in the long run. Our results, which were consistent with the competition for transcriptional resources among neighboring genes, revealed a previously unappreciated facet of the position effect, and highlighted its impact on the fate of genomic integration of exogenous genes, which has profound implications for biological engineering and pathology of virus integrative to host genome.

genomics↗

bioRxiv2020

Organized cannabinoid receptor distribution in neurons revealed by super-resolution fluorescence imaging

G-protein-coupled receptors (GPCRs) play important roles in cellular functions. However, their intracellular organization is largely unknown. Through investigation of the cannabinoid receptor 1 (CB1), we discovered periodically repeating clusters of CB1 hotspots within the axons of neurons. We observed these CB1 hotspots interact with the membrane-associated periodic skeleton (MPS) forming a complex crucial in the regulation of CB1 signaling. Furthermore, we found that CB1 hotspot periodicity increased upon CB1 agonist application, and these activated CB1 displayed less dynamic movement compared to non-activated CB1. Our results suggest that CB1 forms periodic hotspots organized by the MPS as a mechanism to increase signaling efficacy when being activated.

neuroscience↗

bioRxiv2020

Systemic characterization of pppGpp, ppGpp and pGpp targets in Bacillus reveal SatA converts (p)ppGpp to pGpp to regulate alarmone composition and signaling

The alarmones pppGpp and ppGpp (collectively (p)ppGpp) protect bacterial cells from nutritional and other stresses. Here we demonstrate the physiological presence of pGpp as a third closely related alarmone in bacterial cells and also characterize and compare the proteomic targets of pGpp, ppGpp and pppGpp in Gram-positive Bacillus species. We revealed two regulatory pathways for ppGpp and pppGpp that are highly conserved across bacterial species: inhibition of purine nucleotide biosynthesis and control of ribosome assembly/activity through GTPases. Strikingly, pGpp potently regulates the purine biosynthesis pathway but does not interact with the GTPases. Importantly, we identified a key enzyme NahA that efficiently produces pGpp by hydrolyzing (p)ppGpp, thus tuning alarmone composition to uncouple the regulatory modules of the alarmones. Correspondingly, a nahA mutant displays significantly reduced pGpp levels and elevated (p)ppGpp levels, slower growth recovery from nutrient downshift, and loss of competitive fitness. These cellular consequences for regulating alarmone composition strongly implicate an expanded repertoire of alarmones in a new strategy of stress response in Bacillus and its relatives.

microbiology↗

bioRxiv2020

Reusable and Sensitive Detection Method for Exonuclease III Activity by DNB Nanoarrays Based on cPAS Sequencing Technology

AbstractionIn this article, we have designed a sensitive and recycled DNB (DNA nanoball) nanoarrays sequencing complex structures based on BGISEQ-500RS sequencer for the monitoring performance of Exo III activity. In the shortage of Exo III, the effective number ratio of DNB would be captured by an optical system due to one fluorescent. In contrast, in the presence of Exo III, some DNB would disappear or discard from the fields of the optical system by fluorescence extinction and uncleaned fluorescent, respectively. As a result, the effective number of DNB of this strategy was relative to the concentration of Exo III. For Exo III, our strategy showed a highly sensitive linear response in the low detection range of 0.01 U/mL to 0.5 U/mL, with detection limits below 0.01 U/mL. With the comparison between DNB nanoarrays and other fluorescent sensors, this study possessed superior sensitivity, selectivity, and reusability, accompanying with the low cost and simple setup.

biochemistry↗

bioRxiv2020

AfRip3, a RIP3-like kinase, is identified as a key modulator of necroptotic death in Aspergillus fumigatus

Aspergillus fumigatus exhibits autophagic and necroptotic process when its GPI anchor synthesis is suppressed. A putative kinase (AFUA_6G02590) is found to be overexpressed in response to GPI anchor suppression and identified as a RIP3-like protein, namely AfRip3. To elucidate its function, in this study a Afrip3-overexpressing strain OE-Afrip3 was constructed. Although OE-Afrip3 strain exhibited an increased cell death, neither apoptotic nor autophagic process was activated. Our evidences demonstrated that overexpression of Afrip3 gene in A. fumigatus only led to necroptosis, while the Afrip3-knockout mutant was unable to activate necroptotic process. Further analysis revealed that both JNK and SMase pathways were activated in OE-Afrip3 strain, by which an increase of reactive oxygen species (ROS) was induced. We also showed that expression of Afrip3 gene was induced by Ca2+. In addition, eEF1B{gamma} and adenylylsulfate kinase (ASK) were identified as potential candidates to interact with AfRip3. These results indicate that AfRip3 is a key modulator that activates necroptotic process in A. fumigatus, which can be induced by Ca2+ and in turn activate JNK (c-Jun NH2-terminal kinase) and SMase (sphingomyelinase) pathway. Our findings suggest that necroptotic pathway in A. fumigatus is distinct from that in mammalian cell and may provide a new strategy for development of anti-fungal drug. Author summaryAspergillus fumigatus is a human fungal pathogen and causes invasive aspergillosis (IA) in immunocompromised patients with high mortality (30-95%). Development of novel therapies is urgently needed. In this study, we confirm AfRip3 (AFUA_6G02590), a RIP3-like protein, is a key modulator that activates necroptotic process in A. fumigatus. We also find that cytosolic Ca2+ can induce the expression of Afrip3 and activated AfRip3 in turn activate JNK (c-Jun NH2-terminal kinase) and SMase (sphingomyelinase) pathway. Our findings suggest that necroptotic pathway in A. fumigatus is distinct from that in mammalian cell and may provide a new strategy for development of anti-fungal drug.

microbiology↗

bioRxiv2020

Negative feedback between the APC/C and Cep152 at the centrosome regulates mitotic spindle assembly

The control of protein abundance is a fundamental regulatory mechanism during mitosis. The anaphase promoting complex/cyclosome (APC/C) is the main protein ubiquitin ligase responsible for the temporal regulation of mitotic progression. It has long been speculated that the APC/C might fulfil other functions including assembly of the mitotic spindle. Here, we show that the APC/C localizes to centrosomes, the organizers of the eukaryotic microtubule cytoskeleton, specifically during mitosis. The APC/C is recruited to spindle poles by the centrosomal protein Cep152, and we identified Cep152 as both a novel APC/C interaction partner, and as an APC/C substrate. Importantly, this revealed a mitotic function of Cep152 that is reciprocally regulated by the APC/C. A destruction-defective mutant of Cep152 showed that the timely regulation of Cep152 levels at the centrosome controls spindle assembly and chromosome segregation. The APC/C-mediated degradation of Cep152 at the centrosome releases Cep57 from an inhibitory complex to enable its interaction with pericentrin, a critical step in promoting microtubule nucleation. Thus, our study extends the function of the APC/C from being a regulator of mitosis to also acting as a positive governor of spindle assembly. The APC/C thereby integrates control of these two important processes in a temporal manner.

cell biology↗

bioRxiv2020

Sustained Release of IL-2 Using an Injectable Hydrogel Prevents Autoimmune Diabetes

Interleukin 2 (IL-2) is a promising therapy for autoimmune type 1 diabetes (T1D), but the short half-life in vivo (less than 6 minutes) limits effective tissue exposure to IL-2. Tissue exposure is required for the tolerogenic effects of IL-2. We have developed an injectable hydrogel that incorporates heparin polymers to enable the sustained release of IL-2. This platform uses clinical grade and commercially available materials, including collagen, hyaluronan, and heparin, to deliver IL-2 by slowly degrading and releasing IL-2 over a two-week period in vivo. We find that heparin potentiates the activity of IL-2 and IL-2-mediated expansion of Foxp3+ regulatory T cell (Treg). Hydrogel-mediated IL-2 release showed a reduction of CD4+ and CD8+ T cells and an increase of FoxP3+ Treg in the lymph nodes of injected mice. Moreover, in the Non-Obese Diabetic (NOD) mouse model of T1D once-weekly administration of IL-2 hydrogels prevented diabetes onset as efficiently as 3x weekly repeated injections of soluble IL-2. Together these data suggest that heparin-containing hydrogels may have benefit in delivering low-dose IL-2 and promoting immune tolerance in autoimmune diabetes.

immunology↗

bioRxiv2020

DeepDigest: prediction of protein proteolytic digestion with deep learning

In shotgun proteomics, it is essential to accurately determine the proteolytic products of each protein in the sample for subsequent identification and quantification, because these proteolytic products are usually taken as the surrogates of their parent proteins in the further data analysis. However, systematical studies about the commonly used proteases in proteomics research are insufficient, and there is a lack of easy-to-use tools to predict the digestibilities of these proteolytic products. Here, we propose a novel sequence-based deep learning model - DeepDigest, which integrates convolutional neural networks and long-short term memory networks for digestibility prediction of peptides. DeepDigest can predict the proteolytic cleavage sites for eight popular proteases including trypsin, ArgC, chymotrypsin, GluC, LysC, AspN, LysN and LysargiNase. Compared with traditional machine learning algorithms, DeepDigest showed superior performance for all the eight proteases on a variety of datasets. Besides, some interesting characteristics of different proteases were revealed and discussed.

bioinformatics↗

bioRxiv2020

Adaptive evolution of DNA methylation reshaped gene regulation in maize

DNA methylation is a ubiquitous chromatin feature -- in maize, more than 25% of cytosines in the genome are methylated. Recently, major progress has been made in describing the molecular mechanisms driving methylation, yet variation and evolution of the methylation landscape during maize domestication remain largely unknown. Here we leveraged whole-genome sequencing (WGS) and whole genome bisulfite sequencing (WGBS) on populations of modern maize, landrace, and teosinte (Zea mays ssp. parviglumis) to investigate the adaptive and phenotypic consequences of methylation variations in maize. By using a novel estimation approach, we inferred the methylome site frequency spectrum (mSFS) to estimate forward and backward epimutation rates and selection coefficients. We found weak evidence for direct selection on DNA methylation in any context, but thousands of differentially methylated regions (DMRs) were identified in population-wide that are correlated with recent selection. Further investigation revealed that DMRs are enriched in 5 untranslated regions, and that maize hypomethylated DMRs likely helped rewire distal gene regulation. For two trait-associated DMRs, vgt1-DMR and tb1-DMR, our HiChIP data indicated that the interactive loops between DMRs and respective downstream genes were present in B73, a modern maize line, but absent in teosinte. Functional analyses suggested that these DMRs likely served as cis-acting elements that modulated gene regulation after domestication. Our results enable a better understanding of the evolutionary forces acting on patterns of DNA methylation and suggest a role of methylation variation in adaptive evolution.

plant biology↗

bioRxiv2020

Novel Bayesian transcriptome-wide association study method leveraging both cis- and trans- eQTL information through summary statistics

Transcriptome-wide association studies (TWAS) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans- expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian Genome-wide TWAS (BGW-TWAS) method which leverages both cis- and trans- eQTL information for TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans- eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWAS achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N=[~]3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of gene ZC3H12B and Alzheimers dementia (AD) (p-value= 5.42 x 10-13), neurofibrillary tangle density (p-value= 1.89 x10-6 ), and global measure of AD pathology (p-value=9.59 x 10-7). These associations for gene ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of gene KCTD12 was found to be significantly associated with {beta}-amyloid (p-value= 3.44 x10 -8) which was driven by both cis- and trans- eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within gene APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N=[~]54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.

genetics↗