Functional & Integrative Genomics最新文献

{"title":"Single-cell and spatial transcriptomic landscapes reveal PIGT as a pivotal regulator of immunometabolic remodeling in colorectal cancer liver metastasis","authors":"Mengzhu Yan,&nbsp;Yixing Li,&nbsp;Yun Liu,&nbsp;Lilan Peng,&nbsp;Haibo Zhou","doi":"10.1007/s10142-026-01990-1","DOIUrl":"10.1007/s10142-026-01990-1","url":null,"abstract":"<div><p>Colorectal cancer liver metastasis (CRLM) represents the leading cause of mortality in colorectal cancer (CRC). However, the molecular mechanisms enabling metastatic adaptation within the hepatic microenvironment remain unclear. We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk transcriptomic data from CRC patients to characterize the immunometabolic landscape of CRLM. Machine learning models were used to identify key regulators, and functional assays were conducted to validate their biological roles. Nine major cell populations were delineated within CRLM, revealing enrichment of myeloid-derived suppressor cells and depletion of fibroblasts in metastatic lesions. Malignant cells displayed pronounced chromosomal instability and metabolic reprogramming. Among candidate regulators, PIGT emerged as a pivotal node linking metabolic adaptation and immune suppression. PIGT expression increased progressively from primary to metastatic states and was associated with immunosuppressive MIF, SPP1, and TGFβ signaling. Spatial transcriptomics demonstrated colocalization of PIGT-high tumor cells with ITGAM⁺ and CD163⁺ macrophages. Functionally, PIGT knockdown significantly suppressed cell invasion, migration, proliferation, and wound healing in vitro. Conversely, transcriptomic and qPCR analyses showed that PIGT-low tumors exhibited higher expression of inflammatory genes enriched in the IL-17 and TNF signaling pathways. Our integrative multi-omics and experimental analyses identify PIGT as a central regulator bridging tumor metabolism and immune modulation in CRLM. These findings highlight PIGT as a promising prognostic biomarker and potential therapeutic target for metastatic colorectal cancer.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-026-01990-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systems-level genomic analyses reveal shared mechanisms underlying endometriosis and sleep disorders","authors":"Licong Shen,&nbsp;Jun Chen,&nbsp;Yongwen Yang","doi":"10.1007/s10142-026-01979-w","DOIUrl":"10.1007/s10142-026-01979-w","url":null,"abstract":"<div><p>We examined clinical, genetic, and molecular links between sleep disorders and endometriosis. Women aged 20–54 years in NHANES 2005–2006 were analyzed with survey-weighted logistic regression. Bidirectional two-sample Mendelian randomization (MR) was used to assess genetic directionality. Endometriosis-related genes were obtained from the Endometriosis eQTL analysis, whereas sleep disorder-related proteins were obtained from the sleep disorder pQTL analysis and mapped to their encoding genes. The two candidate lists were intersected by gene symbol, and shared candidates were evaluated by pathway enrichment, transcriptomic validation, machine-learning prioritization, single-cell localization, drug-gene annotation, and exploratory docking. Among 1,460 women, clinician-diagnosed sleep disorder was more common in those with endometriosis than in those without endometriosis (weighted prevalence, 13.4% vs 5.1%). In the core adjusted model, endometriosis was associated with higher odds of clinician-diagnosed sleep disorder (OR 2.64, 95% CI 1.03–6.76; <i>P</i> = 0.044). Forward MR suggested a modest association between genetic liability to sleep disorders and endometriosis risk (IVW OR 1.11, 95% CI 1.00–1.22; <i>P</i> = 0.040), whereas reverse MR provided no clear evidence for the opposite direction. Intersecting endometriosis-related eQTL genes with sleep disorder-related pQTL protein-coding genes yielded 37 shared xQTL-prioritized gene/protein candidates. Downstream analyses highlighted glucose metabolism, MAPK signaling, inflammatory pathways, and stromal-cell expression of SPARC and YEATS4. Sleep disorders and endometriosis showed convergent epidemiologic, genetic, and expression-based signals. The core clinical association remained positive after adjustment for major demographic and lifestyle covariates. The genetic and molecular findings should be interpreted as hypothesis-generating pending prospective and experimental validation.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Multi-omics analysis positions DNA2 at the interface of genome integrity programs and tumor behavior in pan-cancer","authors":"Depanshi Pandit,&nbsp;Amardeep Dhillon,&nbsp;Sanjiban Chakrabarty,&nbsp;Ravindranath Sanganabasappa Bilachi","doi":"10.1007/s10142-026-01962-5","DOIUrl":"10.1007/s10142-026-01962-5","url":null,"abstract":"","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANGPTL4 in gestational diabetes: a diagnostic biomarker linked to placental senescence","authors":"Yu-Feng He,&nbsp;Hui Chen,&nbsp;Chuan-Meng Zhang,&nbsp;Su-Su Yang,&nbsp;Xiao-Long Yang,&nbsp;Li-Shuai Jiang,&nbsp;Fan Wang,&nbsp;Shu-Guang Zhou","doi":"10.1007/s10142-026-01978-x","DOIUrl":"10.1007/s10142-026-01978-x","url":null,"abstract":"<div><p>Current diagnostic methods for Gestational Diabetes Mellitus (GDM) inadequately reflect early placental pathophysiology. Accelerated cellular senescence in trophoblasts has been reported as a pathological feature associated with the GDM placenta. However, the potential of senescence-related genes (SRGs) as candidate biomarkers or molecular indicators for GDM has not been systematically investigated. Placental transcriptomic data from GDM and control samples were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed senescence-related genes (DE-SRGs) were identified. A classification model was built using an integrative machine learning framework, and RT-qPCR validated model gene expression in placental tissues. In parallel, a prospective nested case-control study (30 GDM cases and 30 controls) was conducted, with peripheral blood collected in the first trimester, second trimester, and at delivery. Plasma Angiopoietin-like 4 (ANGPTL4) levels were measured by ELISA to determine the key gene for downstream investigation. Single-cell RNA sequencing (scRNA-seq) was then used to resolve the cellular expression patterns and cell–cell communication networks of the key gene. (Chinese Clinical Trial Registration No. ChiCTR2400091955; Registration Date: 2024-11-06). The classification model integrating <i>ANGPTL4</i> and <i>DST</i> demonstrated favorable retrospective discriminatory performance (training set AUC = 0.95; validation set AUC = 0.87). This model served as a discovery tool rather than a clinical predictor. RT-qPCR indicated upregulation of <i>ANGPTL4</i> in GDM placentas (<i>P</i> &lt; 0.05), ANGPTL4 was significantly elevated in the first trimester of women who later developed GDM (P_adj = 0.038); this difference was no longer significant in the second trimester. Accordingly, <i>ANGPTL4</i> was prioritized for further study, <i>ANGPTL4</i> was predominantly expressed in extravillous trophoblasts (EVTs), where its expression positively correlated with cellular senescence. Cell communication analysis predicted potential ligand–receptor interactions between <i>ANGPTL4</i> and <i>ITGA5</i>/<i>ITGB1</i>/<i>SDC4</i> in EVTs. DE-SRGs in GDM placentas were highly enriched in lipid metabolism pathways, aligning with <i>ANGPTL4</i>‘s known function. Integrating machine learning with single-cell transcriptomics, we identified placental senescence-related gene candidates associated with GDM. ANGPTL4 is elevated in first‑trimester plasma and enriched in extravillous trophoblasts, where its expression correlates with lipid metabolism and cellular senescence signatures. These correlative findings generate testable hypotheses linking ANGPTL4‑mediated signaling to placental senescence. <i>ANGPTL4</i> emerges as a candidate biomarker whose clinical potential warrants further evaluation in prospective cohorts.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics identification of SPON1-related risk model for predicting prognosis and drug response in ovarian cancer","authors":"Zouyu Zhao,&nbsp;Yajing Yu,&nbsp;Liansuo Zhang,&nbsp;Wei Shao,&nbsp;Mingqing Li,&nbsp;Jinzhi Li,&nbsp;Songping Liu","doi":"10.1007/s10142-026-01967-0","DOIUrl":"10.1007/s10142-026-01967-0","url":null,"abstract":"<div><p>Ovarian cancer (OC) is a highly lethal gynecological malignancy owing to late-stage diagnosis, high recurrence and metastasis rate. Spondin-1 (SPON1), a secreted extracellular matrix protein, has been demonstrated to be over-expressed in multiple tumors. However, the carcinogenic mechanism of SPON1 in OC remains unclear. Differential expression analysis was employed to identify SPON1-related genes from public databases. Immunohistochemistry (IHC) was utilized to detect SPON1 protein expression. Kaplan–Meier analysis was applied to evaluate the survival differences. Least absolute shrinkage and selection operator and Cox analysis were used to construct risk model. The C-index, receiver operating characteristic curve, calibration curve and decision curve analysis were performed to evaluate the predictive efficacy. Enrichment analysis revealed biological processes. Additionally, the relationships between risk score and tumor microenvironment (TME), somatic mutations and drug sensitivity were assessed. SPON1 was significantly upregulated in OC samples, and high SPON1 expression was associated with worse survival rate. Then a six-gene risk model was conducted in training set. The prognostic accuracy of model was validated using multiple external cohorts. Functional analysis indicated that multiple cancer progression and immune-related pathways were markedly associated with the risk score. The infiltration levels of most immune cells were decreased in the high-risk subgroup. High-risk patients displayed poor response to common drugs for chemotherapy and decreased tumor mutation burden in OC. In summary, we developed and validated a SPON1-based risk model for predicting the prognosis of OC patients and explored the differences in the TME and response to chemotherapy.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell and spatial transcriptomics identify CAPG as a key driver of cisplatin resistance in bladder cancer","authors":"Jianwei Yang,&nbsp;Xiaoran Li,&nbsp;Li Wang,&nbsp;Shun Wan,&nbsp;Kunpeng Li,&nbsp;Siyu Chen,&nbsp;Shanhui Liu,&nbsp;Li Yang","doi":"10.1007/s10142-026-01988-9","DOIUrl":"10.1007/s10142-026-01988-9","url":null,"abstract":"<div><p>Cisplatin-based chemotherapy is widely used for bladder cancer, yet therapeutic resistance remains a major clinical obstacle. Here, by integrating cisplatin-related single-cell RNA sequencing datasets with spatial transcriptomics, we identified distinct malignant cell populations associated with cisplatin resistance. These resistant states exhibited enhanced stemness features, increased intercellular communication, and metabolic adaptation. Building on these resistance-associated cellular programs, we applied a cross-platform screening strategy incorporating urinary proteomics and transcriptomic profiling of cisplatin-resistant bladder cancer cells to prioritize clinically relevant resistance-associated genes. Through this approach, macrophage capping protein (CAPG) emerged as a key resistance-associated regulator. CAPG expression was consistently elevated in cisplatin-resistant tumors and cell models. Functional studies demonstrated that CAPG depletion suppressed malignant phenotypes, restored cisplatin sensitivity, and reduced IC₅₀ values in vitro, with concordant tumor-suppressive effects observed in xenograft models. Mechanistically, CAPG promoted cisplatin resistance, at least in part, through activation of the PI3K–AKT signaling pathway. Together, our study links resistance-associated cellular states to a functionally validated regulator and provides an integrative framework for identifying clinically relevant regulators of chemotherapy resistance in bladder cancer.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative multi-omics analysis identifies FAM3D as a prognostic tumor suppressor in cervical cancer","authors":"Yanbin Chen,&nbsp;Yu Hong,&nbsp;Dongjun Wei,&nbsp;Lianjiao Fan,&nbsp;Dian Tao,&nbsp;Rui Zhang,&nbsp;Hongwei Yang","doi":"10.1007/s10142-026-01955-4","DOIUrl":"10.1007/s10142-026-01955-4","url":null,"abstract":"<div><p>Cervical cancer (CC) remains a leading malignancy among women worldwide. Epigenetic and transcriptional dysregulation complicate the identification of causal genes with prognostic and therapeutic relevance. We performed a multi-omics integrative analysis combining summary data-based Mendelian randomization (SMR) using eQTL and pQTL datasets with genome-wide association study (GWAS) summary statistics (ID: ukb-b-8777) to prioritize candidate genes associated with CC. Differential expression analyses were conducted using multiple GEO cohorts, and protein expression was validated by immunohistochemistry (IHC) in clinical specimens. DNA methylation profiling and correlation analyses were performed using GEO and TCGA datasets to investigate epigenetic regulation. Kaplan–Meier and combined expression–methylation survival analyses were used to evaluate prognostic significance. Functional validation was conducted in HeLa cells using wound-healing and CCK-8 assays following FAM3D knockdown or overexpression. RNA sequencing was further performed to explore the downstream molecular pathways regulated by FAM3D. Integrative SMR analysis identified FAM3D as a protective gene for CC. FAM3D expression was significantly reduced in CC tissues and exhibited a progressive decline from normal cervical tissues to cervical intraepithelial neoplasia (CIN) and invasive CC, which was further confirmed by IHC. Promoter hypermethylation of FAM3D (cg26334888) was associated with its transcriptional downregulation and negatively correlated with gene expression. Survival analyses demonstrated that high FAM3D expression (<i>p</i> = 0.016) and low promoter methylation (<i>p</i> = 0.048) were associated with favorable overall survival, while combined expression–methylation analysis further improved prognostic stratification (<i>p</i> = 0.006). Functional assays showed that FAM3D suppressed CC cell proliferation and migration. Transcriptomic profiling revealed that FAM3D restoration induced extensive transcriptional reprogramming and was associated with inflammatory signaling, cytokine-mediated pathways, and extracellular matrix remodeling. Key hub genes identified downstream of FAM3D included CXCL8, MMP1, EREG, and LCN2. FAM3D is a potential tumor suppressor and prognostic biomarker in CC, whose expression is partially regulated by promoter methylation. Integrative multi-omics analyses and functional studies suggest that FAM3D may inhibit CC progression through modulation of inflammatory signaling and extracellular matrix-associated pathways. These findings provide new insights into the molecular mechanisms underlying CC and support the potential clinical utility of FAM3D as a prognostic biomarker and therapeutic target.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a stromal myeloid-fibrotic index and a tumor-intrinsic immune evasion index for molecular stratification in colorectal cancer","authors":"Ismahane Abdelaziz,&nbsp;Badr-Eddine Allal,&nbsp;Bahia Djerdjouri,&nbsp;Abdelkader Bounaama","doi":"10.1007/s10142-026-01983-0","DOIUrl":"10.1007/s10142-026-01983-0","url":null,"abstract":"<div><p>Immune checkpoint blockade has limited efficacy in microsatellite-stable colorectal cancer, where immune resistance may reflect stromal remodeling, tumor-intrinsic immune evasion, or both. Bulk classifications such as the Consensus Molecular Subtypes can mix these mechanisms into discrete labels. We developed two continuous indices computable from bulk data, a stromal myeloid fibrotic index (SMI) based on TGFβ signaling and an SPP1⁺ macrophage program, and a residualized immune evasion index (IEI_resid) combining CIN70 with reduced antigen presentation after adjustment for tumor purity and immune content. Across three cohorts (<i>n</i> = 1,243), SMI was associated with macrophage abundance, while IEI_resid was associated with lower antigen presentation scores. In CPTAC COAD, SMI aligned with extracellular matrix and stromal protein markers, whereas IEI_resid aligned with reduced antigen presentation proteins and a composite APM protein score. SMI and IEI_resid improved model fit beyond CMS and beyond ESTIMATE stromal and immune scores. Spatial transcriptomics in two independent tumors provided supportive evidence for compartment-level separation of stromal and epithelial programs and higher immune signal in stromal-dominant regions. These results provide a practical framework to model stromal remodeling and tumor-intrinsic antigen presentation features as partially separable dimensions in colorectal cancer.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A reproducible endothelial-state contrast with limited bulk prognostic robustness in hepatocellular carcinoma","authors":"Si-yuan Tan,&nbsp;Lan-hui Qin,&nbsp;Wenqing Liang,&nbsp;Rui Song,&nbsp;Pei-yin Chen,&nbsp;Weihui Xu,&nbsp;Guanzhen Zeng,&nbsp;Yu Zhang,&nbsp;Liling Long","doi":"10.1007/s10142-026-01989-8","DOIUrl":"10.1007/s10142-026-01989-8","url":null,"abstract":"<div><p>Endothelial-cell (EC) states may influence the hepatocellular carcinoma (HCC) microenvironment, but EC-derived bulk-tissue scores can also capture tumour purity and cellular admixture. We re-derived and stress-tested a previously proposed vascular immune accessibility score. GSE149614 was analysed with sample-aware doublet detection, ambient-RNA correction, pan-cell-type specificity testing, and patient-level pseudobulk contrasts. A deterministic algorithm selected two 15-gene modules. Independent single-cell validation used GSE151530, with all score genes excluded from unsupervised tumour endothelial-cell (TEC) clustering. Bulk sensitivity analyses used TCGA-LIHC, GSE14520, and ICGC LIRI-JP; TCGA models incorporated ABSOLUTE purity. Spatial analyses used two unique GSE245908 sections. Only 9/25 original immune-adhesive genes and 6/25 barrier genes passed EC-specificity thresholds. GSE151530 included 50,023 HCC cells from 25 patients and 32 specimens, including 2,299 quality-controlled TECs. At the patient level, both modules were EC enriched (median TEC-minus-non-TEC differences 1.438 and 3.222; paired Wilcoxon <i>P</i> = 2.21 × 10^-5 and 1.94 × 10^-5). The modules mapped onto 12 independently derived TEC clusters. The revised score correlated modestly with TCGA ABSOLUTE purity (rho=-0.137; <i>P</i> = 0.010). Clinical Cox models were non-significant in TCGA-LIHC, GSE14520, and ICGC LIRI-JP, and cohort directions were inconsistent. Spatial results replicated in only one of two sections. The revised score was not evaluable in the 24-sample NanoString immunotherapy cohort because only 3/30 genes were present. The reproducible result is an LSEC-like-to-angiogenic EC transcriptomic contrast. The data do not support direct immune-accessibility, directionally consistent prognostic, or immunotherapy-selection claims.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative exome sequencing and multi-omics analysis elucidates the regulatory role of rare variants in metabolic syndrome","authors":"Cheng-Xi Wu,&nbsp;Jin Sang,&nbsp;Qian Xu,&nbsp;Ya Zhan,&nbsp;Shan-Juan Yuan,&nbsp;Yuan-Yuan Ge,&nbsp;Xiu-Juan Yu,&nbsp;Xiao Zheng,&nbsp;Xiao-Feng Wang,&nbsp;Xian-Mei He,&nbsp;Chao-Jie Liu,&nbsp;Yuan Luo,&nbsp;Lei Zhang,&nbsp;Yu-Fang Pei","doi":"10.1007/s10142-026-01987-w","DOIUrl":"10.1007/s10142-026-01987-w","url":null,"abstract":"<div><p>Metabolic syndrome (MetS) is a cluster of interconnected cardiometabolic risk factors with a substantial but incompletely characterized genetic basis. To identify novel genetic determinants, particularly rare variants, we here conducted a large-scale exome-wide association study in 367,188 individuals from the UK Biobank (78,300 cases and 288,888 controls). Single-variant analysis identified 74 independent loci, three of which correspond to rare variants in CARMIL2, ACTR6, and PLA2G12A without prior documented MetS association. Furthermore, gene-based burden testing pinpointed three key genes: ABCA1, APOC3, and PDE3B. Integrative follow-up analyses - including colocalization across molecular traits (mRNA, protein, microbiota) and association testing with proteomic/metabolic biomarkers - collectively suggest that these rare variants influence MetS susceptibility through coordinated effects on protein expression, metabolite concentrations, and microbial abundance. Importantly, ABCA1, APOC3, and PDE3B are established or promising drug targets for related metabolic disorders. In summary, our study not only elucidates the significant contribution of rare variants to MetS susceptibility, distinct from common variant signals, but also highlights the central role of lipid metabolism pathways, thereby nominating plausible targets for therapeutic intervention. Clinical trial number:Not applicable.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}