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Breast cancer is a common malignant tumor with a complex pathogenesis, and while genome-wide association studies (GWAS) have identified multiple risk loci, they often fall short in pinpointing specific functional susceptibility genes. To address this, we collected whole-tissue eQTL data from the GTEx portal and breast cancer GWAS summary data from the Breast Cancer Association Consortium (BCAC) and FinnGen R10 database, employing transcriptome-wide association studies (TWAS) to screen and identify susceptibility genes. Subsequently, spatial transcriptomic sequencing and single-cell RNA sequencing were employed to investigate the underlying mechanisms of these genes within the tumor microenvironment (TME) and their relevance as therapeutic targets. We identified five susceptibility genes-ADCY3, CASP8, GRHL1, HELQ, and TLR1-which are enriched in tumor-related signaling pathways such as Kras and TNFα. In the breast cancer TME, these genes are associated with myofibroblasts, mast cells, and M2 macrophages, and these cells may interact via biological pathways involving macrophage migration inhibitory factor (MIF) and secreted phosphoprotein 1 (SPP1). Notably, TLR1 may serve as a drug target, with compounds such as Doxorubicin and Etoposide identified as potential candidates. In conclusion, ADCY3, CASP8, GRHL1, HELQ, and TLR1, as genetic susceptibility genes for breast cancer, hold significant value in understanding tumor development and advancing therapy. Show less

A narrow range of food consumption and/or restricted eating is a core feature of avoidant/restrictive food intake (ARFI) disorder. However, there is limited knowledge of developmental characteristics of children with ARFI and its etiological influences, which constrains research, prevention, and intervention efforts. To estimate the prevalence of ARFI phenotypes in a population-based sample, examine developmental characteristics across childhood, and investigate the genetic architecture of ARFI using genome-wide association analyses. This preregistered study used data from children born from 1999 to 2009 in the population-based Norwegian Mother, Father, and Child Cohort Study (MoBa), with mother-reported data on ARFI symptoms at 3 and 8 years and linkage with diagnostic data from population health registries. Data were analyzed from March 2024 to May 2025. Multiple items were used to identify children with broad ARFI. These children were subclassified into 3 groups based on symptom persistence: ARFI-broad transient (only at age 3 years), emergent (only at age 8 years), and persistent (ages 3 and 8 years). Children in these groups with 1 or more indicators of clinical significance (eg, nutritional deficiency) were further classified into ARFI-clinical subgroups. ARFI groups were compared across developmental characteristics from 6 months to 14 years. Genome-wide methods were used to examine single-nucleotide variant (SNV) heritability (SNV-h2), conduct genetic association analyses, and quantify genetic correlations with other phenotypes. Of 35 751 children with available ARFI assessments at 3 and 8 years (18 236 male [51%]), the prevalence of ARFI-broad persistent, transient, and emergent was 2129 (6.0%), 6338 (17.7%), and 3001 (8.4%), respectively. The prevalence of ARFI-clinical persistent, transient, and emergent was 624 (1.8%), 1157 (3.2%), and 484 (1.4%), respectively (2265 [6.3%] overall). Children with ARFI-broad persistent exhibited more developmental difficulties compared with children with no ARFI. SNV-h2 ranged from 8% to 16%. Two independent genome-wide significant loci were identified. For ARFI-clinical, a significant association was identified with ADCY3 (z = 5.42; P = 3.03 × 10-8). Small to moderate genetic correlations were observed for ARFI-broad, ARFI-clinical and mental health, cognitive/educational, anthropometric, food-associated, and gastrointestinal disorder phenotypes. This cohort study found that the prevalence of ARFI in the general pediatric population was substantial, and affected children had an associated elevated risk of developmental difficulties across multiple domains. Findings suggest a need for broad support interventions and advance understanding of the genetic underpinnings of ARFI. Show less

Human genetic analyses have identified numerous single-nucleotide polymorphism (SNP) loci in noncoding regions associated with obesity-related traits; however, the functional contributions of such SNP loci to obesity are largely unknown. The noncoding variant rs713586, with its risk allele C, is linked to two candidate genes, DNAJC27 and ADCY3, potentially implicated in obesity. However, whether rs713586 primary targets ADCY3 or DNAJC27 gene to regulate body weight and what molecular mechanisms underlie this process remain unclear. We conducted bioinformatics analyses using BMI data from the UK biobank and GIANT consortium, and prioritised functional variants on chromosome 2 linked to ADCY3 gene for experimental validation. The variant rs713586 was identified as a functional regulator of ADCY3 and DNAJC27 expression. We investigated the molecular mechanisms by which rs713586 participates in obesity through epigenetic regulation. Dual-luciferase reporter assay and genome-editing in cell lines were conducted to assess the impacts of the rs713586-C risk allele or a proximal enhancer (Enh) on ADCY3 and DNAJC27 promoter activity and expression levels. CRISPR/Cas9-mediated knockout of Dnajc27 was performed in mice to evaluate its role in obesity. Mechanistic studies examined the interactions between the rs713586-T or -C alleles and the transcription factor ZFP42. Additionally, we assessed the DNA methylation patterns within the Enh and promoter regions of ADCY3 to evaluate their impact on ADCY3 expression. First, the rs713586-C risk allele significantly reduced the promoter activity of ADCY3 and DNAJC27 and thus reduced their expression levels. However, Dnajc27 knockout mice did not develop obesity, thereby excluding DNAJC27 as the target gene through which rs713586 mediates obesity. Further, we demonstrate that the rs713586-C allele impaired ZFP42 binding, leading to decreased TET1 recruitment and increased DNA methylation in the Enh and promoter regions of ADCY3, ultimately suppressing its expression. Given that ADCY3 is a well-established gene involved in obesity, we conclude that the rs713586-C risk allele may associated with obesity susceptibility, concomitant with downregulated ADCY3 expression. Our findings establish the rs713586-ZFP42-TET1-ADCY3 epigenetic regulatory axis, providing insights into the mechanism of rs713586-mediated obesity pathogenesis. National Natural Science Foundation of China and Natural Science Foundation of Hebei Province of China (32470645, 32070567, 32202840), and Priority-Funded Postdoctoral Research Project, Zhejiang Province (ZJ2025118). Full funding details are provided in the Acknowledgements. Show less

Genome-wide association studies (GWASs) have identified hundreds of obesity-associated SNPs, but establishing their causality remains challenging. Here, we demonstrate that rs11676272, located in the ADCY3 gene, is a functional causal variant for obesity susceptibility. Bioinformatic analyses and dual-luciferase reporter assays indicate that the rs11676272 region may act as a human-gained enhancer regulating ADCY3 expression. In HEK293T cells, CRISPR-Cas9-mediated single-nucleotide editing of rs11676272 (T > C) reduces ADCY3 expression. Moreover, the rs11676272-T allele is preferentially bound by the transcription factor E2F3 to upregulate ADCY3 expression, whereas the rs11676272-C risk allele loses this binding. In vivo, the rs11676272 T > C variant in human ADCY3 (hADCY3) knock-in mice accelerates weight gain under high-fat diet conditions and shortens primary cilia in the ventromedial hypothalamus (VMH). CRISPRa-mediated activation of the hADCY3 promoter region rescues ciliary length in both the VMH and hypothalamic arcuate nucleus of Mut-hADCY3 mice. Our data reveal a causal role for rs11676272 in obesity, offering insight into potential therapeutic strategies. Show less

Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder. We identified a protein-coding variant in the transmembrane (TM) helix of Adcy3 in rats; similar obesity variants have been identified in humans. This study investigates the role of a TM variant in adiposity and behavior. We mutated the TM domain of Adcy3 (Adcy3 Adcy3 The ADCY3 TM domain plays a role in protein function via p-AMPK and CREB signaling. Adcy3 may contribute to the relationship between obesity and major depressive disorder, and sex influences the relationships between Adcy3, metabolism, and behavior. Show less

Women with autoimmune diseases (AIDs) experience chronic immune dysregulation and hormonal fluctuations, both of which may influence breast cancer risk. However, it remains unclear whether this risk is driven mainly by its treatment or the underlying disease, highlighting the need for integrating real-world data and genetic evidence. The FDA Adverse Event Reporting System (FAERS) were utilized to identify breast cancer safety signals among women with AIDs, analyzing 11,479 reports from 2004 to 2024. Disproportionality analyses using Reporting Odds Ratio (ROR) and Information Component (IC) were conducted. Then, we mapped these drugs to their target genes and performed mendelian randomization (MR) to assess their causal relationships with breast cancer. Finally, we investigated shared genetic architecture between breast cancer and AIDs using global and local genetic correlation, cross-trait meta-analysis, and transcriptome-wide association studies. We identified 13 immunosuppressive drugs (TNF inhibitors, interleukin inhibitors, and monoclonal antibodies), 3 immunostimulants and 16 adjunctive drugs associated with increased breast cancer reporting in patients with AIDs. The drugs with the highest case reports for positive disproportionality analysis were interferon beta-1a (N: 1731, IC [IC025] 1.56 [1.49]), natalizumab (798, 0.65 [0.54]), and infliximab (741, 0.64 [0.53]). MR results revealed causal links between 9 drug targets and breast cancer risk, such as FDPS (OR: 0.66, p: 1.33E-08), CALCRL (OR: 0.887, p: 4.77E-06) and PARP1 (OR: 1.051, p: 3.50E-06). Global genetic correlation identified significant shared heritability between breast cancer and 3 specific AIDs, including type 1 diabetes mellitus (rg: -0.242, p: 0.95E-4), ulcerative colitis (rg: 0.125, p: 0.29E-2), and migraine (rg: 0.078, p: 0.79E-2). Specifically, the most notable genetic overlap was observed between breast cancer and type 1 diabetes mellitus, with significant shared risk SNPs (rs12046289 and rs6679677) and susceptibility genes (ADCY3 and CENPO). Our study uncovered several immune-related drugs associated with increased breast cancer reporting in women with AIDs. This risk may be explained by several potential drug targets with causal roles, or by the shared genetic comorbidity between specific AIDs and breast cancer. These insights emphasize the need for tailored breast cancer surveillance and highlight potential molecular targets for intervention in vulnerable populations. Show less

Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY-cAMP-PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY-PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes. Show less

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less

Breast cancer, a major threat to women's health worldwide, has mechanisms of onset that remain unclear. Within the human lysosomal system, a class of enzymes known as cathepsins exhibit elevated expression levels in various malignant tumors, suggesting that they may play key roles in cancer progression. This study employed the two-sample Mendelian randomization (MR) approach to investigate the potential causal relationship between cathepsin levels and the risk of developing breast cancer. Furthermore, we conducted MR analysis using eQTL data to investigate how gene expression, mediated by cathepsins, affects the occurrence of different types of breast cancer and assessed the regulatory effects of cathepsins. MR analysis revealed that increased levels of cathepsin E are associated with a greater risk of malignant breast tumors (IVW: p = 0.006, OR = 1.103, 95% CI = 1.028-1.184), and increased levels of cathepsin F are associated with an increased risk of These findings highlight the dual roles of cathepsins as potential risk and protective factors for breast cancer, underscoring their potential in diagnostic and therapeutic strategies. Show less

Adipose tissue-derived mesenchymal stromal/stem cells (ASCs) possess regenerative potential. Obesity induces a pro-inflammatory environment that compromises their function. Here we investigate how obesity affects ASC biology, focusing on primary cilia. Our data show that obesity alters ASC gene expression, particularly in pathways related to the extracellular matrix, transforming growth factor-β (TGFβ) signaling, cell motility, and differentiation. The gene levels of regulatory factor X2 (RFX2) and adenylate cyclase 3 (ADCY3), important for ciliary biogenesis, are downregulated in obese ASCs. TGFβ treatment significantly decreases the expression of RFX2 and ADCY3 in lean ASCs. Knockdown of ADCY3 reduces primary cilium length, whereas pharmacological activation restores it and improves cell motility. These results suggest that obesity impairs ASC ciliary function, contributing to defective adipogenesis and reduced regenerative capacity. Restoring ADCY3 activity partially rescues ciliary integrity and cellular function, highlighting the role of primary cilia in ASC dysfunction and offering potential therapeutic targets for obesity-related disorders. Show less

We have previously demonstrated that a transmembrane domain mutation in Adenylate cyclase 3 (Adcy3) causes increased adiposity and negative emotion-like behaviors in a rat model. We set out to replicate and expand upon our previous study by conducting comprehensive behavioral testing, and we also investigated the molecular changes that result from this mutation. Rats with a mutation in the second transmembrane helix of ADCY3 (Adcy3 Show less

One of the recognized effects of systematic physical activity is the improvement of physical fitness, with a negative correlation found between physical fitness and cardiovascular and cardiometabolic risk. The purpose of this study is to analyze the influence of single nucleotide polymorphisms (SNPs) of the adenylate cyclase 3 ( In the 12-week HIIT program, a total of 237 Chinese Han college students with non-regular exercise habits were recruited, and these volunteers participated in the training three times a week. Baseline and after the HIIT program, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured, respectively. DNA was extracted from the white blood cells of volunteers and genotyping was carried out. The PLINK v1.09 software was used to conduct quality control screening on the obtained SNPs, and a linear regression model was constructed to analyze the association between (1) Through the analysis of Illumina CGA chip scanning, a total of 22 SNPs of the (1) The implementation of a 12-week HIIT regimen can significantly enhance the blood lipid status of college students. (2) The locus rs2241759 of the Show less

Excessive adipose tissue accumulation adversely impacts the health of both humans and livestock. Adenylyl cyclase 3 (ADCY3) is a promising anti-obesity target, yet its regulatory role in adipogenesis remains incompletely understood. Our findings revealed a dynamic pattern of ADCY3 expression during adipogenesis and lipid droplet (LDs) accumulation. Functional analyses demonstrated that ADCY3 overexpression impaired adipogenesis by downregulating adipogenic transcription factors CEBPα and PPARγ. Furthermore, it reduced both the number and size of LDs through suppressing triglyceride synthesis and fatty acid metabolism, concomitantly downregulating key genes involved in LDs formation (PLIN1, CIDEC, FIT2, and Seipin), as well as factors mediating glycerol ester synthesis and fatty acid metabolism (DGAT1, DGAT2, ACC, SCD, FASN, and ACSL1). Transcriptomic profiling revealed that ADCY3 overexpression suppressed PPARγ signaling, leading to the downregulation of oxidative phosphorylation genes encoded by both the nuclear and mitochondrial genomes. Our results implicate ADCY3 in the regulation of lipid metabolism, with the speculative involvement of mitochondrial metabolic remodeling. This perspective offers a framework for developing future interventions against excessive lipid deposition. Show less

Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat. Milk-derived exosomes, particularly those from sheep milk (SM-Exo), have shown potential in treating gastrointestinal disorders, though their efficacy in Cd-induced colitis remains unclear. In this study, we investigated the therapeutic potential of SM-Exo in a Cd-induced colitis model. Hu sheep were exposed to Cd, and their fecal microbiota were collected to prepare bacterial solutions for fecal microbiota transplantation (FMT) in mice. The changes in gut microbiota and gene expression were analyzed through microbiome and transcriptomics. Our results showed that prior to treatment, harmful bacteria (e.g., Show less

Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave adaptation by comparing brain transcriptomes of sympatric cave-dwelling ( Show less

Colorectal cancer (CRC) is widely recognized for its high prevalence and significant mortality rates, and purine metabolism has been serving as a potential therapeutic target. However, purine metabolism has not yet been validated as a prognostic marker through immunohistochemical analysis. In this study, we utilized a combination of bulk transcriptome analysis, immunohistochemistry (IHC), and single-cell RNA sequencing (scRNA-seq) to assess the clinical relevance of purine metabolism in CRC. Low expression levels of five purine metabolism-related genes-ADSL, APRT, ADCY3, NME3, and NME6-were associated with worse prognosis in CRC patient subgroups, including wild-type TP53, mutant TP53, and microsatellite-stable phenotypes. IHC-based validation showed that NME3 expression was an independent prognostic factor, whereas ADSL and NME6 expressions were associated with clinical variables in prediction of prognosis. Notably, NME3 expression predicted a high risk in patients with early-stage CRC, while ADSL and NME6 expressions were predictive in late-stage CRC. scRNA-seq analysis showed that four genes, excluding NME6, had low expression levels in epithelial cells at the late-stage CRC. Despite the reversible nature of purine metabolism reactions, we demonstrated a consistent directional expression of these five prognostic purine metabolism-related proteins in CRC tissues. We suggest that alterations in purine metabolism could serve as a clinically useful prognostic marker in CRC. Show less

Primordial follicle formation and activation are key for the reproductive ability of females. In mice, primordial follicles are formed and begin to activate during the perinatal period, when the levels of estrogen are fluctuating. Whether estrogen plays a role in primordial follicle formation and activation, and its mechanism are still not fully elucidated. In this study, estrogen remained at high levels before birth and declined after birth. When fetal mouse ovaries (E16.5) were cultured in vitro, higher levels (10 nM) of estrogen maintained the germ cell cysts, prevented primordial follicles from forming prematurely, and promoted the full differentiation of oocytes. Furthermore, it was found that estrogen-regulated JNK-signal pathway through both nuclear and membrane receptors, thereby inhibited the degradation of E-cadherin and maintained the germ cell cysts. After birth, ovarian estrogen concentration decreases and is accompanied by the activation of primordial follicles. Hence, the ovaries of newborn mice (P3) were treated with lower concentrations (0.1 nM) of estrogen to investigate the effect of estrogen on primordial follicle activation. The results demonstrated that estrogen regulated the protein expression of cAMP synthase adenylyl cyclase 3 (ADCY3) through the membrane receptor G-protein-coupled estrogen receptor (GPER), increased the level of cAMP in the ovary, and activated the cAMP-PKA signaling pathway to promote the activation of primordial follicles. This study revealed the regulatory role of perinatal estrogen levels on primordial follicle formation and activation before and after birth, which would help to better understand the potential physiological effect of estrogen in vivo. Show less

The Golgi apparatus (GA) serves as the center of protein and lipid synthesis and modification within cells, playing a crucial role in regulating diverse cellular processes as a signaling hub. Dysregulation of GA function can give rise to a range of pathological conditions, including tumors. Notably, mutations in Golgi-associated genes (GARGs) are frequently observed in various tumors, and these mutations have been implicated in promoting tumor metastasis. However, the precise relationship between GARGs and glioma, a type of brain tumor, remains poorly understood. Therefore, the objective of this investigation was to assess the prognostic significance of GARGs in glioma and evaluate their impact on the immune microenvironment. The expression of GARGs was obtained from the TCGA and CGGA databases, encompassing a total of 1564 glioma samples (598 from TCGA and 966 from CGGA). Subsequently, a risk prediction model was constructed using LASSO regression and Cox analysis, and its efficacy was assessed. Additionally, qRT-PCR was employed to validate the expression of GARGs in relation to glioma prognosis. Furthermore, the association between GARGs and immunity, mutation, and drug resistance was investigated. A selection of GARGs (SPRY1, CHST6, B4GALNT1, CTSL, ADCY3, GNL1, KIF20A, CHP1, RPS6, CLEC18C) were selected through differential expression analysis and Cox analysis, which were subsequently incorporated into the risk model. This model demonstrated favorable predictive efficiency, as evidenced by the area under the curve (AUC) values of 0.877, 0.943, and 0.900 for 1, 3, and 5-year predictions, respectively. Furthermore, the risk model exhibited a significant association with the tumor immune microenvironment and mutation status, as well as a diminished sensitivity to chemotherapy drugs. qRT-PCR analysis confirmed the up-regulation or down-regulation of the aforementioned genes in glioma. The utilization of GARGs in our constructed model exhibits a high level of accuracy in prognosticating glioma and offers promising avenues for the development of therapeutic interventions targeting glioma. Show less

Patients with obstructive sleep apnea (OSA) experience chronic intermittent hypoxia (CIH). OSA patients and CIH-treated rodents exhibit overactive sympathetic nervous system and hypertension, mediated through hyperactive carotid body (CB) chemoreflex. Activation of olfactory receptor 78 (Olfr78) by hydrogen sulfide (H2S) is implicated in CB activation and sympathetic nerve responses to CIH, but the downstream signaling pathways remain unknown. Given that odorant receptor signaling is coupled to adenylyl cyclase 3 (Adcy3), we hypothesized that Adcy3-dependent cyclic adenosine monophosphate (cAMP) contributes to CB and sympathetic responses to CIH. Our findings show that CIH increases cAMP levels in the CB, a response absent in Adcy3, Cth (encoding CSE), and Olfr78 null mice. CBs from Cth and Olfr78 mutant mice lacked a persulfidation response to CIH, indicating that Adcy3 activation requires Olfr78 activation by H2S in CIH. CIH also enhanced glomus cell Ca2+ influx, an effect absent in Cnga2 (encoding cyclic nucleotide-gated channel alpha2 subunit) and Adcy3 mutants, suggesting that CIH-induced cAMP mediates enhanced Ca2+ responses through cyclic nucleotide-gated channels. Furthermore, Adcy3 null mice did not exhibit either CB activation or sympathetic activation by CIH. These results demonstrate that Adcy3-dependent cAMP is a downstream signaling pathway to H2S/Olfr78, mediating CIH-induced CB activation, sympathetic activity and hypertension. Show less

Ulcerative colitis (UC) is a prevalent chronic gastrointestinal disease. Gene plays an important role in UC pathogenesis. Therefore, we aim to identify UC susceptibility genes and specific cell types expressing these genes. We conducted a cross-tissue transcriptome-wide association study by integrating UC GWAS with 49 tissues gene expression matrix from the Genotype-Tissue Expression project. Subsequently, we employed Functional Summary-based Imputation to verify candidate genes within colon tissue. Conditional and Joint Analysis was utilized to filter out genes potentially influenced by linkage disequilibrium. Multimarker Analysis of Genomic Annotation was then applied to pinpoint genes relevant to UC. Validation of the selected genes was performed using Mendelian randomization. GeneMANIA analysis was conducted to elucidate biological functions of identified genes. Finally, single-cell RNA sequencing was employed to ascertain cell types in which these genes are enriched. The cross-tissue transcriptome-wide association study, Functional Summary-based Imputation and Multimarker Analysis of Genomic Annotation analyses identified a total of 5 genes, of which 3 genes, ADCY3, ITGB6, and MTMR3, were retained after Mendelian randomization. These genes were found to be implicated in several functional pathways, including the cyclic AMP metabolic process and phosphorus-oxygen lyase activity. Furthermore, we observed ADCY3 predominantly enriched in B cells, while ITGB6 and MTMR3 enriched in epithelial cells. Our study has identified 3 genes associated with UC susceptibility. These findings not only enhance our understanding of the genetic underpinnings of UC, but also offer novel avenues for exploring molecular mechanisms and potential therapeutic targets for UC. Show less

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the Show less

Sepsis, characterized as a systemic inflammatory response triggered by pathogen invasion, represents a continuum that may progress from mild systemic infection to severe sepsis, potentially culminating in septic shock and multiple organ dysfunction syndrome. A pivotal element in the pathogenesis and progression of sepsis involves the significant disruption of oncological metabolic networks, where cells within the pathological milieu exhibit metabolic functions that diverge from their healthy counterparts. Among these, purine metabolism plays a crucial role in nucleic acid synthesis. However, the contribution of Purine Metabolism Genes (PMGs) to the defense mechanisms against sepsis remains inadequately explored. Leveraging bioinformatics, this study aimed to identify and substantiate potential PMGs implicated in sepsis. The approach encompassed a differential expression analysis across a pool of 75 candidate PMGs. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were employed to assess the biological significance and pathways associated with these genes. Additionally, Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) methodologies were implemented to identify key hub genes and evaluate the diagnostic potential of nine selected PMGs in sepsis identification. The study also examined the correlation between these hub PMGs and related genes, with validation conducted through expression level analysis using the GSE13904 and GSE65682 datasets. The study identified twelve PMGs correlated with sepsis, namely AK9, ENTPD3, NUDT16, GMPR2, PKM, RRM2B, POLR2J, POLE3, ADCY3, ADCY4, ADSSL1, and AMPD1. Functional analysis revealed their involvement in critical processes such as purine nucleotide and ribose phosphate metabolism. The diagnostic capability of these PMGs to effectively differentiate sepsis cases underscored their potential as biomarkers. This research elucidates twelve PMGs associated with sepsis, providing valuable insights into novel biomarkers for this condition and facilitating the monitoring of its progression. These findings highlight the significance of purine metabolism in sepsis pathogenesis and open avenues for further investigation into therapeutic targets. Show less

This study aims to identify new variants and haplotypes associated with monogenic obesity by analyzing known obesity genes in whole exome sequencing (WES) data. The monogenic obesity-associated genes were identified by using the National Institutes of Health (NIH) Genetic Testing Registry (GTR) monogenic obesity panels. WES was performed on ( Seventy-four genes were included in WES analyses. After Bonferroni correction, the T allele of rs2275155 on This study suggested that the T allele of two common variants rs2275155 and rs116167439, also rare variant rs201676524 are associated with an increased risk of monogenic obesity. The significant haplotype associations indicate these variants may be in linkage with causative rare variants and should be considered in future studies. The online version contains supplementary material available at 10.1007/s40200-024-01507-2. Show less