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Childhood obesity is one of the most common and costly nutritional problems with high heritability. The genetic mechanism of childhood obesity remains unclear. Here, we conducted a transcriptome-wide association study (TWAS) to identify novel genes for childhood obesity. By integrating the GWAS summary of childhood body mass index (BMI), we conducted TWAS analyses with pre-computed gene expression weights in 39 obesity priority tissues. The GWAS summary statistics of childhood BMI were derived from the early growth genetics consortium with 35,668 children from 20 studies. We identified 15 candidate genes for childhood BMI after Bonferroni corrections. The most significant gene, ADCY3, was identified in 13 tissues, including adipose, brain, and blood. Interestingly, eight genes were only identified in the specific tissue, such as FAIM2 in the brain (P = 2.04 × 10 Our study identified multiple candidate genes for childhood BMI, providing novel clues for understanding the genetic mechanism of childhood obesity. Show less

Tuberculosis (TB) is one of the leading causes of childhood morbidity and death globally. Lack of rapid, effective non-sputum diagnosis and prediction methods for TB in children are some of the challenges currently faced. In recent years, blood transcriptional profiling has provided a fresh perspective on the diagnosis and predicting the progression of tuberculosis. Meanwhile, combined with bioinformatics analysis can help to identify the differentially expressed genes (DEGs) and functional pathways involved in the different clinical stages of TB. Therefore, this study investigated potential diagnostic markers for use in distinguishing between latent tuberculosis infection (LTBI) and active TB using children's blood transcriptome data.From the Gene Expression Omnibus database, we downloaded two gene expression profile datasets (GSE39939 and GSE39940) of whole blood-derived RNA sequencing samples, reflecting transcriptional signatures between latent and active tuberculosis in children. GEO2R tool was used to screen for DEGs in LTBI and active TB in children. Database for Annotation, Visualization and Integrated Discovery tools were used to perform Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis. STRING and Cytoscape analyzed the protein-protein interaction network and the top 15 hub genes respectively. Receiver operating characteristics curve was used to estimate the diagnostic value of the hub genes.A total of 265 DEGs were identified, including 79 upregulated and 186 downregulated DEGs. Further, 15 core genes were picked and enrichment analysis revealed that they were highly correlated with neutrophil activation and degranulation, neutrophil-mediated immunity and in defense response. Among them TLR2, FPR2, MMP9, MPO, CEACAM8, ELANE, FCGR1A, SELP, ARG1, GNG10, HP, LCN2, LTF, ADCY3 had significant discriminatory power between LTBI and active TB, with area under the curves of 0.84, 0.84, 0.84, 0.80, 0.87, 0.78, 0.88, 0.84, 0.86, 0.82, 0.85, 0.85, 0.79, and 0.88 respectively.Our research provided several genes with high potential to be candidate gene markers for developing non-sputum diagnostic tools for childhood Tuberculosis. Show less

Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/ Show less

How animals, particularly livestock, adapt to various climates and environments over short evolutionary time is of fundamental biological interest. Further, understanding the genetic mechanisms of adaptation in indigenous livestock populations is important for designing appropriate breeding programs to cope with the impacts of changing climate. Here, we conducted a comprehensive genomic analysis of diversity, interspecies introgression, and climate-mediated selective signatures in a global sample of sheep and their wild relatives. By examining 600K and 50K genome-wide single nucleotide polymorphism data from 3,447 samples representing 111 domestic sheep populations and 403 samples from all their seven wild relatives (argali, Asiatic mouflon, European mouflon, urial, snow sheep, bighorn, and thinhorn sheep), coupled with 88 whole-genome sequences, we detected clear signals of common introgression from wild relatives into sympatric domestic populations, thereby increasing their genomic diversities. The introgressions provided beneficial genetic variants in native populations, which were significantly associated with local climatic adaptation. We observed common introgression signals of alleles in olfactory-related genes (e.g., ADCY3 and TRPV1) and the PADI gene family including in particular PADI2, which is associated with antibacterial innate immunity. Further analyses of whole-genome sequences showed that the introgressed alleles in a specific region of PADI2 (chr2: 248,302,667-248,306,614) correlate with resistance to pneumonia. We conclude that wild introgression enhanced climatic adaptation and resistance to pneumonia in sheep. This has enabled them to adapt to varying climatic and environmental conditions after domestication. Show less

To investigate the differentially expressed genes (DEGs) and molecular interaction in unstable atherosclerotic carotid plaques. Gene expression datasets GSE41571, GSE118481, and E-MTAB-2055 were analyzed. Co-regulated DEGs in at least two datasets were analyzed with the enrichment of Gene Ontology Biological Process (GO-BP), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) networks, interrelationships between miRNAs/transcriptional factors, and their target genes and drug-gene interactions. The expression of notable DEGs in human carotid artery plaques and plasma was further identified. The GO-BP enrichment analysis revealed that genes associated with inflammatory response, and extracellular matrix organization were altered. The KEGG enrichment analysis revealed that upregulated DEGs were enriched in the tuberculous, lysosomal, and chemokine signaling pathways, whereas downregulated genes were enriched in the focal adhesion and PI3K/Akt signaling pathway. Collagen type I alpha 2 chain (COL1A2), adenylate cyclase 3 (ADCY3), C-X-C motif chemokine receptor 4 (CXCR4), and TYRO protein tyrosine kinase binding protein (TYROBP) might play crucial roles in the PPI networks. In drug-gene interactions, colonystimulating factor-1 receptor had the most drug interactions. Insulin-like growth factor binding protein 6 (IGFBP6) was markedly downregulated in unstable human carotid plaques and plasma. Under a receiver operating characteristic curve analysis, plasma IGFBP6 had a significant discriminatory power (AUC, 0.894; 95% CI, 0.810-0.977), with a cutoff value of 142.08 ng/mL. The genes COL1A2, ADCY3, CXCR4, and TYROBP are promising targets for the prevention of unstable carotid plaque formation. IGFBP6 may be an important biomarker for predicting vulnerable plaques. Show less

The bHLH transcription factor Olig2 is required for sequential cell fate determination of both motor neurons and oligodendrocytes and for progenitor proliferation in the central nervous system. However, the role of Olig2 in peripheral sensory neurogenesis remains unknown. We report that Olig2 is transiently expressed in the newly differentiated olfactory sensory neurons (OSNs) and is down-regulated in the mature OSNs in mice from early gestation to adulthood. Genetic fate mapping demonstrates that Olig2-expressing cells solely give rise to OSNs in the peripheral olfactory system. Olig2 depletion does not affect the proliferation of peripheral olfactory progenitors and the fate determination of OSNs, sustentacular cells, and the olfactory ensheathing cells. However, the terminal differentiation and maturation of OSNs are compromised in either Olig2 single or Olig1/Olig2 double knockout mice, associated with significantly diminished expression of multiple OSN maturation and odorant signaling genes, including Omp, Gnal, Adcy3, and Olfr15. We further demonstrate that Olig2 binds to the E-box in the Omp promoter region to regulate its expression. Taken together, our results reveal a distinctly novel function of Olig2 in the periphery nervous system to regulate the terminal differentiation and maturation of olfactory sensory neurons. Show less

As in many autoimmune diseases, the pathogenesis of the antiphospholipid syndrome (APS) is the result of a complex interplay between predisposing genes and triggering environmental factors, leading to a loss of self-tolerance and immune-mediated tissue damage. While the first genetic studies in APS focused primarily on the Show less

Fructus has motivation effect on gastrointestinal tract. Hesperidin is extracts of Fructus, and we attempted to prove its effects on improving the gastrointestinal transmission function and determine the possible mechanisms by a loperamide-induced slow transit constipation (STC) model. Constipation phenotypes were measured in rats with Lop-induced constipation after treatment with hesperidin. The amounts and water content of stool were significantly higher in the hesperidin-treated group than the loperamide-induced model group, whereas food intake was maintained at constant levels. Moreover, intestinal transit rate was increased in the treatment group of hesperidin. Histological alteration was detected by H&E staining, we found that the colon smooth muscle cells and neuron cells of the rats were increased, and the infiltration of inflammatory cells was decreased in the hesperidin-treated group compared with the loperamide-induced model group. 5-Hydroxytryptamine (5-HT) receptor4 fluorescence intensity and intracellular-free calcium ions in colon tissue were increased, and relative protein of cAMP/PKA pathway and p-cAMP response component-binding protein (CREB) pathway were upregulated in the hesperidin-treated group compared with the loperamide-induced model group. Further, SMCs from colon tissue of rats were cultured and identified. We found hesperidin could significantly promote tegaserod-induced increase of 5-HTR4 fluorescence intensity, intracellular calcium ions, relative protein of cAMP/PKA pathway and p-CREB pathway, and cell proliferation and inhibit GR113808-induced decrease of 5-HTR4 fluorescence intensity, 5-HTR4 pathway-related proteins (ADCY3, cAMP, PKA, and p-CREB), intracellular calcium ions, and cell proliferation. The analysis of our data suggested that hesperidin could obviously improve the gastrointestinal transmission function in loperamide-induced STC rat model via increasing the 5-HTR4 and intracellular-free calcium ions to enhance the expression of relative protein of cAMP/PKA pathway and p-CREB pathway. Hesperidin could be used in the treatment of STC, and our data not only provide experimental basis for the treatment of STC in hesperidin but also provides a theoretical reference for clinical treatment. Show less

Adenylate cyclases (ADCYs) catalyze the conversion of ATP to cAMP, an important co-factor in energy homeostasis. Giving ADCYs role in obesity, diabetes and inflammation, we questioned whether calcium-stimulated ADCY isoforms may be variably detectable in human plasma. We report the results of a cross-sectional study assessing circulating levels of functional ADCY1, -3 and -8 in patients with T2D vs. non-diabetic (ND) controls in association with obesity. ADCY1 levels exhibited no significant change between ND and T2D groups. ADCY3 levels were lower in obese individuals, albeit not statistically significantly. In contrast, ADCY8 plasma levels were significantly higher in obese and T2D patients compared to controls ( Show less

Glioblastoma (GBM) is a common and aggressive primary brain tumor, and the prognosis for GBM patients remains poor. This study aimed to identify the key genes associated with the development of GBM and provide new diagnostic and therapies for GBM. Three microarray datasets (GSE111260, GSE103227, and GSE104267) were selected from Gene Expression Omnibus (GEO) database for integrated analysis. The differential expressed genes (DEGs) between GBM and normal tissues were identified. Then, prognosis-related DEGs were screened by survival analysis, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed to explore the hub genes associated with GBM. The mRNA and protein expression levels of hub genes were respectively validated in silico using The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases. Subsequently, the small molecule drugs of GBM were predicted by using Connectivity Map (CMAP) database. A total of 78 prognosis-related DEGs were identified, of which10 hub genes with higher degree were obtained by PPI analysis. The mRNA expression and protein expression levels of Our study provided 10 key genes for diagnosis, prognosis, and therapy for GBM. These findings might contribute to a better comprehension of molecular mechanisms of GBM development, and provide new perspective for further GBM research. However, specific regulatory mechanism of these genes needed further elaboration. Show less

Obesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits. This study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers. This study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci. This study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing. Show less

C-type natriuretic peptide (CNP) and its natriuretic peptide receptors subtype 2 (NPR2) are essential for the maintenance of oocyte meiotic arrest in different species. Extracellular vesicles (EVs) in bovine follicular fluid (FF) are important for cell communication within the ovarian follicle. This study investigated the involvement of EVs from FF of bovine ovarian follicles in the CNP-NPR2 system, first by analyzing the presence of CNP in the EV contents, followed by addition of EVs to in-vitro maturation (IVM) medium, to evaluate the effect on maintenance of oocyte meiosis arrest and improvements in in-vitro embryo production. As expected, CNP was observed in FF and granulosa cells from the ovarian follicles. To the best of our knowledge, this is the first time that CNP has been found in the EV contents. To evaluate the possible effect of EVs on the progression of oocyte meiosis, the IVM was performed under three conditions: CNP and EV supplementation and control condition. Both the CNP and EV treatments inhibited meiosis resumption in the oocyte within 9 h of IVM. CNP treatment increased cGMP levels in cumulus cells within 6 h of IVM compared to the control group, but the EV treatment did not. In contrast, the relative mRNA abundance of adenylate cyclase 3 and 9 (ADCY3 and ADCY9) was upregulated in oocytes after 6 h of IVM under EV treatment compared to the control group, but not under CNP treatment. Last, these treatments in the IVM medium had no significant effect on the in-vitro embryo production. In conclusion, we demonstrated the presence of endogenous CNP in bovine reproductive structures, especially in the EVs from the FF of antral follicles. The presence of CNP in the EVs suggests an important involvement of this cell-communication system in the CNP-NPR2 system. Therefore, we indeed observed that the EVs from FF can modulate the arrest of oocyte meiosis, acting similarly to the CNP-NPR2 system to block the oocyte in the GV state. However, the mechanism of each system might be different; the CNP-NPR2 system seems to be involved in modulating the cGMP levels, while the contents of EVs might be involved in modulating the cAMP levels. Show less

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features. Show less

Lifestyle choices such as the intake of sweets, history of diseases, and genetic variants seem to play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). To explore which genetic and environmental factors are associated with NAFLD in a Chinese Han population, we conducted this study. We collected the medical reports, lifestyle details, and blood samples of individuals and used the polymerase chain reaction-ligase detection reaction method to genotype the single-nucleotide polymorphism (SNPs) from the 2113 eligible people. The GG genotype of the additive model of rs7493 in the PON2, the CC genotype of the additive and recessive models of rs7593130 in the ADCY3, together with dyslipidemia, regular intake of egg and sweets and hypertension, increased the risk of NAFLD (adjusted OR > 1, Show less

To explore the effect of miR-335-5p/ADCY3 interaction on the lymphocyte function in the patients with aplastic anemia (AA). Blood samples were collected from 22 healthy volunteers (HC) and 50 AA patients including 38 severe AA (SAA) and 12 non-severe AA (NSAA). Peripheral blood mononuclear cells (PBMNC) were isolated. The expression of miR-335-5p and ADCY3 mRNA was detected by using RT-PCR. Negative control miR-335-5p (NC group) and miR-335-5p mimic (mimic group) were transfected to AA-PBMNC by using RNAimax reagent, respectively. The proliferative ability, activation and cytokines of CD4 The expression of miR-335-5p was significantly downregulated in SAA-PBMNC and NSAA-PBMNC compared with HC-PBMNC (0.08±0.01 vs 0.74±0.10, P＜0.01; 0.17±0.02 vs 0.74±0.10, P＜0.01). Meanwhile, the expression of miR-335-5p in SAA-PBMNC was very statistically significantly lower than that in NSAA-PBMNC (P＜0.01). Compared with NC group, upregulation of miR-335-5p in vitro could significantly inhibited the proliferation of CD4 The expression of miR-335-5p was significantly downregulated in AA, and that correlates with disease severity. Up-regulating miR-335-5p can correct the hyperimmune status in AA patients by targeting ADCY3. These changes may relates with the strengthen of inhibition for targeted gene ADCY3. Show less

Several studies have reported the benefits of olfactory training (OT) in the olfactory nervous system of mouse models. Therefore, in this study we performed next-generation sequencing to evaluate the effects of OT on mRNA sequencing in the olfactory area. Mice in each group were administered 300 mg of 3-methylindole per kilogram of mouse weight. The olfactory function was evaluated by a food-finding test once a week. The olfactory neuroepithelium was harvested for histologic examination and protein analysis. Subsequently, data analysis, gene ontology and pathway analysis, quantitative real-time polymerase chain reaction of mRNA, and Western blot analysis were conducted. Mice were divided into 4 groups according to treatment. Control, anosmia, training, and steroid group mice resumed food finding. Olfactory Maker Protein, olfr1507, ADCY3, and GNAL mRNA expression was higher in the olfactory neuroepithelium of OT than anosmia group mice. In total, 26,364 mRNAs were analyzed. Comparison of the results of OT vs anosmia revealed that ADCY8,10, GFAP, NGF, NGFR, GFAP, and BDNF mRNAs were upregulated in the gene ontology. OT improved olfactory function, as indicated by the food-finding test. OT improved the olfactory recovery time to stimulate olfactory nerve regeneration. OT may initially stimulate the olfactory receptor, followed by neurogenesis. Steroid therapy and OT operated under completely different mechanisms in the upregulated gene study. These results indicate that OT may be one of the future modalities for treating olfactory impairment. Show less

The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective strategies for the prevention of weight gain. Here, we investigated the potential of α-cedrene, a volatile sesquiterpene compound derived from cedarwood oil, in regulation of obesity and delineated the mechanisms involved. For the prevention of obesity, C57BL/6 N mice were fed a high-fat diet (HFD) and were orally administered either with vehicle or α-cedrene for 8 weeks. For the therapy of obesity, obese Sprague Dawley rats, induced by a HFD for 8 weeks, were orally treated either with vehicle or α-cedrene for 12 weeks. To determine whether the action of α-cedrene was Adcy3 dependent, Adcy3 heterozygous null mice (Adcy3 Oral α-cedrene administration prevented or reversed HFD-induced obesity and abnormal metabolic aberrations in rodents, without affecting their food intake. Downregulation of Adcy3 expression by small interfering RNA abrogated the beneficial effects of α-cedrene on the oxygen consumption rate and intracellular lipid accumulation in 3T3-L1 adipocytes. Similarly, in Adcy3 Our results highlight the potential of α-cedrene for antiobesity interventions and suggest that the antiobesity effect of α-cedrene is mediated by Adcy3 in adipose tissues. Show less

Vertical transmission of Zika virus (ZIKV) is associated with congenital malformations but the mechanism of pathogenesis remains unclear. Although host genetics appear to play a role, no genetic association study has yet been performed to evaluate this question. In order to investigate if maternal genetic variation is associated with Congenital Zika Syndrome (CZS), we conducted a case-control study in a cohort of Brazilian women infected with ZIKV during pregnancy. A total of 100 women who reported symptoms of zika during pregnancy were enrolled and tested for ZIKV. Among 52 women positive for ZIKV infection, 28 were classified as cases and 24 as controls based on the presence or absence of CZS in their infants. Variations in the coding region of 205 candidate genes involved in cAMP signaling or immune response were assessed by high throughput sequencing and tested for association with development of CZS. From the 817 single nucleotide variations (SNVs) included in association analyses, 22 SNVs in 17 genes were associated with CZS under an additive model (alpha = 0.05). Variations c.319T>C (rs11676272) and c.1297G>A, located at ADCY3 and ADCY7 genes showed the most prominent effect. The association of ADCY3 and ADCY7 genes was confirmed using a Sequence Kernel Association Test to assess the joint effect of common and rare variations, and results were statistically significant after adjustment for multiple comparisons (P < 0.002). These results suggest that maternal ADCY genes contribute to ZIKV pathogenicity and influence the outcome of CZS, being promising candidates for further replication studies and functional analysis. Show less

Our ongoing analyses identifying dysregulated microRNAs (miRNAs) and their controlled target RNAs have shed light on novel oncogenic pathways in pancreatic ductal adenocarcinoma (PDAC). The PDAC miRNA signature obtained by RNA sequencing showed that both strands of pre-miR-130b (miR-130b-5p, the passenger strand and miR-130b-3p, the guide strand) were significantly downregulated in cancer tissues. Our functional assays revealed that miR-130b-5p significantly blocked the malignant abilities of PDAC cell lines (PANC-1 and SW1990), e.g., cancer cell proliferation, migration, and invasion. A total of 103 genes were identified as possible oncogenic targets by miR-130b-5p regulation in PDAC cells based on genome-wide gene expression analysis and in silico database search. Among the possible targets, high expression of 9 genes (EPS8, ZWINT, SMC4, LDHA, GJB2, ZCCHC24, TOP2A, ANLN, and ADCY3) predicted a significantly poorer prognosis of PDAC patients (5-year overall survival, p < 0.001). Furthermore, we focused on EPS8 because its expression had the greatest impact on patient prognosis (overall survival, p < 0.0001). Overexpression of EPS8 was detected in PDAC clinical specimens. Knockdown assays with siEPS8 showed that its overexpression enhanced cancer cell proliferation, migration, and invasion. Analysis of downstream RNA networks regulated by EPS8 indicated that MET, HMGA2, FERMT1, RARRES3, PTK2, MAD2L1, and FLI1 were closely involved in PDAC pathogenesis. Genes regulated by antitumor miR-130b-5p were closely involved in PDAC molecular pathogenesis. Our approach, discovery of antitumor miRNAs and their target RNAs, will contribute to exploring the causes of this malignant disease. Show less

Olfactory dysfunction significantly impedes the life quality of patients. Neuropeptide Y (NPY) is not only a neurotrophic factor in the rodent olfactory system but also an orexigenic peptide that regulates feeding behavior. NPY increases the olfactory receptor neurons (ORNs) responsivity during starvation; however, whether NPY can promote differentiation of human ORNs remains unexplored. This study investigates the effect of NPY on the differentiation of human olfactory neuroepithelial cells in vitro. Human olfactory neuroepithelium explants were cultured on tissue culture polystyrene dishes for 21 days. Then, cells were cultured with or without NPY at the concentration of 0.5 ng/mℓ for 7 days. The effects of treatment were assessed by phase contrast microscopy, immunocytochemistry and western blot analysis. The further mechanism was evaluated with NPY Y1 receptor-selected antagonist BIBP3226. NPY-treated olfactory neuroepithelial cells exhibited thin bipolar shape, low circularity, low spread area, and long processes. The expression levels of Ascl1, βIII tubulin, GAP43 and OMP were significantly higher in NPY-treated cells than in controls (p < 0.05). NPY-treated olfactory neuroepithelial cells expressed more components of signal transduction apparatuses, G Show less

Fish produce and release bile salts as chemical signalling substances that act as sensitive olfactory stimuli. To investigate how bile salts affect olfactory signal transduction in large yellow croaker ( Show less

Many achievements have been made to develop quantitative trait loci (QTLs) and gene-associated single nucleotide polymorphisms (SNPs) to facilitate practical marker-assisted selection (MAS) in aquatic animals. However, the systematic studies of SNPs associated with extreme threshold traits were poor in populations lacking of parental genomic information. Coupling next generation sequencing with bulked segregant analysis (BSA) should allow identification of numerous associated SNPs with extreme phenotypes. In the present study, using combination of SNP frequency difference and Euclidean distance, we conducted linkage analysis of SNPs located in genes involved in immune responses, and identified markers associated with Vibrio anguillarum resistance in turbot (Scophthalmus maximus). A total of 221 SNPs was found as candidate SNPs between resistant and susceptible individuals. Among these SNPs, 35 loci located in immune related genes were genotyped in verification population and 7 of them showed significant association with V. anguillarum resistance in both alleles and genotypes (P < 0.05). Among these 7 genes, PIK3CA-like, CYLD, VCAM1, RhoB and RhoGEF are involved in PI3K/Akt/mTOR pathway and NF-κB pathway, which influence the efficiency of bacteria entering the host and inflammation. SNP-SNP interaction analysis was performed by generalized multifactor dimensionality reduction (GMDR). The combination of SNP loci in RhoB, PIK3CA-like and ADCY3 showed a significant effect on V. anguillarum resistance with the verification rate in the sequencing population up to 70.8%. Taken all, our findings demonstrated the feasibility of BSA-seq approach in identifying genes responsible for the extreme phenotypes and will aid in performing MAS in turbot. Show less

The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization (MR) was then applied using findings from genome-wide association studies (GWAS) to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently used Bayesian multiple-trait colocalization to further interrogate the findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility. Finally, we applied our analysis pipeline genome-wide using summary statistics from large-scale GWAS. Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol, respectively, were particularly insightful. Multiple-trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also affect cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses uncovered evidence of tissue specificity between gene expression in liver tissue and cholesterol levels. Applying our pipeline genome-wide using summary statistics from GWAS uncovered 233 association signals at loci which represent promising candidates for further evaluation. Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease. Show less

Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans Show less