Genes最新文献

{"title":"Integrated Ovarian circRNA, miRNA and mRNA Profiling Identifies Candidate ceRNA Relationships Associated with Late-Laying and Nesting Stages in Wanxi White Geese.","authors":"Kefeng Yang, Tongsheng Yang, Dexing Cui, Tao Jin, Man Ren, Qianqian Hu, Changsheng Jiang, Chunfang Zhao, Shenghe Li","doi":"10.3390/genes17101227","DOIUrl":"https://doi.org/10.3390/genes17101227","url":null,"abstract":"<p><p><b>Background</b>: The pronounced broodiness of Wanxi white geese is associated with rapid ovarian regression and reduced egg production and reproductive efficiency. However, the extent to which circRNAs influence this physiological transition by coordinating ceRNA interactions is not yet well understood. <b>Methods</b>: Here, we generated ovarian microRNA (miRNA) and circRNA expression profiles by RNA sequencing in late-laying (LLG) and nesting (NG) Wanxi white geese and measured serum reproductive hormones. <b>Results</b>: Compared with the late-laying stage, the nesting stage was characterised by pronounced ovarian atrophy. Serum concentrations of oestradiol (E2), progesterone (P4) and luteinising hormone (LH) were lower, whereas the prolactin (PRL) concentration was higher. Transcriptome analysis identified 156 circRNAs and 64 miRNAs that met the nominal differential expressed (DE) criteria. Enrichment analysis associated genes giving rise to DE circRNAs with membrane and junctional structures, cell adhesion, small GTPase regulation, ECM-receptor interaction, adherens junction, focal adhesion and metabolic processes. Conversely, putative targets of DE miRNAs were linked to AMPK, mTOR, TGF-β and Hippo pathways, together with oocyte meiosis. The integration of the RNA datasets and Pearson correlation analysis highlighted several putative ceRNA relationships associated with ovarian functional transition. During the late-laying period, bioinformatic predictions and expression correlations supported the predicted novel_circ_001280-miR-1-y-CPEB1 and novel_circ_005385-miR-187-x-BMP6 relationships involving genes associated with oocyte development and ovarian endocrine function. By contrast, during the nesting period, bioinformatic analyses supported a putative novel_circ_002435/novel_circ_007511-miR-135-x/z-FOXO3 relationship that may be associated with cellular quiescence, stress responses and follicular atresia. The expression profiles of these network components showed stage-associated correlations with circulating reproductive hormone concentrations. <b>Conclusions</b>: Together, these findings suggest an exploratory ceRNA landscape associated with ovarian functional remodelling in Wanxi white geese and identify RNA relationships that warrant further functional validation.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent Acute Liver Failure in Children: A Systematic Review of Genetic Etiologies, Diagnostic Clues, and Liver Transplantation.","authors":"Patryk Lipiński, Piotr Socha, Irena Jankowska","doi":"10.3390/genes17101225","DOIUrl":"https://doi.org/10.3390/genes17101225","url":null,"abstract":"<p><strong>Background: </strong>Recurrent acute liver failure (RALF) is a rare phenotype with heterogeneous inherited causes.</p><p><strong>Methods: </strong>We conducted a PRISMA 2020 systematic review of PubMed/MEDLINE and Web of Science Core Collection. Reports were classified into two non-combinable evidence sets: strict RALF, requiring at least two documented pediatric acute liver failure episodes with recovery of liver synthetic function between episodes, and contextual disease-specific evidence used only to inform broader natural history, treatment, or transplantation.</p><p><strong>Results: </strong>The searches identified 128 records; 30 duplicates were removed, and 98 records were screened. Forty-eight full texts were assessed, and 44 publications representing 41 study or cohort units were retained across both evidence sets. The evidence consisted predominantly of case reports, small case series, and retrospective cohorts, with inconsistent RALF definitions and incompletely reported follow-up. The five-group framework is a pragmatic organization of reported qualifying disorders rather than an exhaustive genetic classification.</p><p><strong>Conclusions: </strong>Genomic testing during a first unexplained severe episode is proposed to avoid waiting for recurrence, but most disorder-specific treatment and transplantation conclusions remain based on limited observational evidence and expert practice.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Consequence of <i>IRF6</i> Variants in Van der Woude Syndrome.","authors":"Mojisola Olujitan, Rose Gogal, Tamara Busch, Chloe Ovel, Anjolaoluwa Awe, Jorge Ceballos, Kikanwa Okiosor, Natalie Ibarra, Emmanuel Aladenika, Waheed Awotoye, Veronica Sule, Babatunde Faparusi, Benjamin Bass, Rishitha Gadde, Thirona Naicker, Lord J J Gowans, Mekonen Eshete, Wasiu Lanre Adeyemo, Aline Petrin, Martine Dunnwald, Carmen J Buxo, Peter Mossey, Michael Schnieders, Azeez Butali","doi":"10.3390/genes17101223","DOIUrl":"https://doi.org/10.3390/genes17101223","url":null,"abstract":"<p><p>Van der Woude syndrome (VWS) is the most common syndromic form of orofacial clefts (OFCs). The heritability of VWS is largely (~70%) explained by variants in the <i>IRF6</i> gene. Experimental studies to confirm genetic variant effects are essential but are time intensive and expensive. Advancing next-generation sequencing techniques has made it possible to identify genetic variation quicker than their causal effects in disease processes can be ascertained. Therefore, employing computational tools to reliably predict their causal effects is crucial for advancing translational research. We conducted Sanger sequencing of the <i>IRF6</i> gene in 46 VWS cases across 34 families to identify likely causal missense variants. We then assessed structure-informed stability changes to the IRF6 protein when these variants were incorporated into the protein, using DDGun3D. We compared DDGun3D predictions to results from previous experimental studies. Among four variants previously shown to prevent functional rescue in zebrafish, only the variant <i>IRF6</i>(NM_006147.4):c.881T>C, shown to cause rupture of zebrafish embryo, exhibited a high free energy change (∆∆G<i>_fold</i> = 3.5 kcal/mol), indicating that substantial predicted thermodynamic destabilization does not capture all disruptive function of IRF6. Our study demonstrates the utility of a protein structure-based computational approach for functional variant interpretation, providing a complementary method for studying genetic variation. Integrating computational predictions with experimental data can enhance our understanding of genetic conditions. However, success depends on fully elucidating protein structures, which is an active area of research.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reticulocalbin-2 (RCN2) as a Context-Dependent CREC-Family Modulator: Gene Expression and Regulation, Molecular Biology, Disease Relevance, and Translational Challenges.","authors":"Abdullah A A Alghamdi","doi":"10.3390/genes17101226","DOIUrl":"https://doi.org/10.3390/genes17101226","url":null,"abstract":"<p><p>Reticulocalbin-2 (RCN2), encoded by the human <i>RCN2</i> gene (HGNC:9935) and historically identified as E6-binding protein, is a CREC-family EF-hand Ca²⁺-binding protein. Although first characterized as an endoplasmic reticulum (ER)-associated protein, current evidence extends RCN2 biology to splice-variant and localization complexity, protein interactions, regulatory and signaling networks, extracellular activity, cancer, non-malignant disease, and the RCN2-derived hormone Raptin. This review synthesizes the fragmented and methodologically uneven RCN2 literature within an evidence-stratified framework. Mechanistic evidence, including direct biochemical assays and RCN2-directed functional studies, supports selected interaction and signaling relationships, whereas omics, database-derived and single-context observations remain hypothesis-generating. Across disease settings, RCN2 is best interpreted as a context-dependent modulator rather than a uniform oncogenic driver, validated biomarker or established therapeutic target. Translational progress will require molecular-form-specific assays, disease-specific validation and clinically grounded models.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apospory Expressivity and Segregation in Intraspecific Hybrids of <i>Paspalum notatum</i> Flügge.","authors":"Andrea Peréz Góez, Carine Simioni, Diógenes Cecchin Silveira, Nair Dahmer, Maria Eduarda Pagani Sangineto, Jonathan Krug, Cristiane Stainhaus, Matheus Bragé Dos Santos, Henrique Ludvig Vogt, Pablo Przyczynski Rauber, Roberto Luis Weiler","doi":"10.3390/genes17101220","DOIUrl":"https://doi.org/10.3390/genes17101220","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Apospory is a key component of gametophytic apomixis in <i>Paspalum notatum</i> and is relevant to breeding because, together with parthenogenesis and appropriate endosperm development, it can enable clonal seed reproduction. This study determined reproductive phenotype at the embryo-sac level, quantified apospory expressivity, and evaluated segregation in tetraploid intraspecific hybrids. <b>Methods:</b> Inflorescences were collected from 84 hybrids from 11 crosses between sexual female and aposporous male parents. Cleared ovaries were examined by differential interference contrast microscopy. Hybrids were classified as facultatively aposporous when at least one ovule contained an aposporous embryo sac; expressivity was calculated as A/(S + A) × 100. <b>Results:</b> Reproductive phenotype was determined in 80 hybrids: 48 were facultatively aposporous and 32 were sexual; four were indeterminate. Expressivity ranged from 3% to 69%. Pooled segregation did not deviate significantly from 1:1 (χ² = 3.20; <i>p</i> = 0.0736), whereas the largest family, KF4 × KF6, deviated from 1:1 (15 S:32 facultatively aposporous; exact <i>p</i> = 0.0186). Between-family heterogeneity was not significant (Monte Carlo exact <i>p</i> = 0.1444). <b>Conclusions:</b> Apospory showed substantial variation in expressivity and family-level segregation. Because parthenogenesis and maternal progeny origin were not evaluated, these results characterize apospory rather than complete apomictic seed reproduction.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Field-Zone-Associated Transcriptomic and Metabolic Divergence Despite Nearly Identical Observed Chlorophyll in an Agrivoltaic Tea Setting.","authors":"Ruifang Wang, Shuai Zhang, Zhengwan Xie, Songsong Shen, Huiping Zhou, Jie Liu","doi":"10.3390/genes17101221","DOIUrl":"https://doi.org/10.3390/genes17101221","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Similar leaf chlorophyll in agrivoltaic tea fields may conceal molecular divergence. <b>Methods:</b> We reanalysed physiology, RNA sequencing and metabolomics from five field zones (three plant-level replicates each), prioritizing T2 versus T3. Missing plot maps and independent installation replicates limited inference to zone associations. <b>Results:</b> T2 and T3 had nearly identical mean total chlorophyll (0.50495 versus 0.50309 mg g^-1; Welch <i>p</i> = 0.920), whereas T2 had higher carotenoids, total sugars, alkaloids, phenols and flavonoids; all five differences had Benjamini-Hochberg false discovery rate (FDR) < 0.05 across 50 physiological tests. Relative to the open-sun control (CK), T2 and T3 had 7 and 6857 differentially expressed genes and 35 and 523 differential unique metabolite profiles, respectively. Omitting one sample from each of T2, T3 and CK yielded 27 combinations, all showing greater transcriptome and metabolome displacement in T3. After adjustment for the leading whole-omics component, exact within-zone permutation supported sample-pattern coupling for glycolysis and porphyrin metabolism (Benjamini-Hochberg FDR = 0.0288 for each). In comparison with four public tea datasets, T1 showed the strongest descriptive rank concordance; T3 showed little concordance. <b>Conclusions:</b> Similar chlorophyll means coexist with divergent molecular profiles. These observational results do not establish effects of photovoltaic hardware.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Regulation and Gut Microbiota Dysbiosis in Age-Related Macular Degeneration.","authors":"Stamatios Lampsas, Chrysa Agapitou, Gerasimia-Marina Chardalia, Dimitrios Soulimiotis, Konstantinos Papastamopoulos, Panagiotis Theodossiadis, Irini Chatziralli","doi":"10.3390/genes17101219","DOIUrl":"https://doi.org/10.3390/genes17101219","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is a leading cause of visual impairment. Beyond the classical pathogenetic pathways, increasing evidence suggests that epigenetic regulation and the gut-retina axis may substantially contribute to AMD development and progression. This review synthesizes current evidence on two increasingly recognized and interconnected domains of AMD pathogenesis: epigenetic regulation and gut microbiota dysbiosis. Epigenetic processes, such as DNA methylation, histone modifications, and non-coding RNAs, can influence gene function involved in oxidative stress responses, complement regulation, angiogenesis, and inflammation, while several related markers have emerged as potential diagnostic and prognostic biomarkers. Moreover, growing evidence suggests a functional gut-retina axis, in which alterations in the gut microbiota impair intestinal barrier function and facilitate the systemic passage of bacteria and microbial metabolites, potentially affecting retinal inflammation and immune responses. Furthermore, several microbial metabolites, including short-chain fatty acids, lipopolysaccharide, bile acids, tryptophan derivatives, and trimethylamine-N-oxide, may have either protective or harmful effects on retinal and choroidal homeostasis, with altered circulating and fecal concentrations reported in patients with AMD compared with controls. These findings support AMD as a systemically and molecularly interconnected disorder, while further longitudinal, mechanistic, and multi-omics studies are required to establish causality, define interactions between epigenetic and microbiome-related pathways, and clarify their potential utility as biomarkers and therapeutic targets.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complementary Genomic and Functional Potential of <i>Bacillus subtilis</i> RKM-1 and <i>Bacillus licheniformis</i> RKM-2 for Organic Waste Bioconversion and Composting.","authors":"Tekebayeva Zhanar, Abilkhadirov Arman, Begakhmet Akbota, Kulzhanova Kamshat, Temirbekova Aliya, Nurbekova Zhadyrassyn, Aslan Temirkhanov, Bekshin Zhandarbek, Abzhalelov Akhan","doi":"10.3390/genes17101222","DOIUrl":"https://doi.org/10.3390/genes17101222","url":null,"abstract":"<p><strong>Background: </strong>Efficient bioconversion of organic waste requires microorganisms with the potential to degrade complex organic compounds and transform biogenic elements.</p><p><strong>Methods: </strong>In this study, two thermophilic bacterial strains, RKM-1 and RKM-2, isolated from sewage sludge, were characterized using whole-genome sequencing and comparative genomics to establish their taxonomic positions and assess their functional potential.</p><p><strong>Results: </strong>RKM-1 and RKM-2 were identified as <i>Bacillus subtilis</i> and <i>Bacillus licheniformis</i>, respectively, with maximum ANI values of 98.76% and 99.76%. Comparative genomic analysis revealed differences in the functional potential of the two strains. RKM-1 exhibited genomic features associated with the transformation of biogenic elements and secondary metabolite biosynthesis, whereas RKM-2 showed greater genetic potential for the utilization and transformation of complex carbohydrates, supported by the presence of genes such as <i>amyA</i>, <i>bglC</i>, <i>celA</i>, <i>glcT</i>, <i>galE</i>, <i>galU</i>, and <i>glgABCD</i>. These differences indicate potentially complementary functional profiles of the two strains in the bioconversion of organic substrates. During sewage sludge composting, inoculation with both strains accelerated the onset of the thermophilic phase. <i>Bacillus subtilis</i> RKM-1 reached the highest compost temperature (60 °C), whereas <i>Bacillus licheniformis</i> RKM-2 most effectively promoted compost maturation, reducing the C:N ratio to 9:1 within 60 days.</p><p><strong>Conclusions: </strong>These findings demonstrate a strong relationship between the genomic characteristics and functional traits of the investigated strains and highlight the value of comparative genomics as a powerful tool for identifying promising thermophilic microorganisms for efficient bioconversion of organic wastes.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-Wide Characterization of the bZIP Gene Family in Winter Jujube Highlights <i>ZjbZIP7</i>'s Association with Late Fruit Development.","authors":"Shumin Li, Li Tian, Hongwei Chen, Huafeng Yue, Gaopu Zhu, Mengmeng Zhang","doi":"10.3390/genes17101217","DOIUrl":"https://doi.org/10.3390/genes17101217","url":null,"abstract":"<p><p><b>Background:</b> Basic leucine zipper (bZIP) transcription factors function widely in plant development, hormone signaling, and fruit ripening, but the bZIP family and its potential regulatory roles in winter jujube fruit development remain poorly characterized. <b>Methods:</b> a genome-wide analysis was performed using the gapless genome assembly of winter jujube (<i>Ziziphus jujuba</i> Mill. cv. Dongzao), including phylogenetic, chromosomal distribution, gene duplication, synteny, gene structure, conserved motif, and promoter cis-element analyses. Developmental expression patterns were investigated using RNA-seq and RT-qPCR. Weighted gene co-expression network analysis (WGCNA) and a yeast one-hybrid assay were further used to examine the co-expression relationships of ZjbZIP7 and its promoter-binding association with <i>ZjACO1</i>. <b>Results:</b> A total of 52 <i>ZjbZIP</i> genes were identified and classified into nine phylogenetic groups. These genes were unevenly distributed across 11 chromosomes, and 11 segmentally duplicated gene pairs were detected. Comparative synteny analysis identified 46 syntenic bZIP gene pairs between winter jujube and the sour jujube (<i>Z. jujuba</i> var. <i>spinosa</i>) and 42 between winter jujube and <i>Arabidopsis thaliana.</i> Promoter analysis identified 53 types of cis-acting elements associated with light, phytohormones, stress responses, and development; notably, abscisic acid-responsive elements were present in 47 of the 52 promoters. RNA-seq analysis across seven fruit developmental stages showed that 18 <i>ZjbZIP</i> genes accumulated preferentially during the late stages, with <i>ZjbZIP7</i> showing particularly pronounced transcript accumulation during the late developmental stages. RT-qPCR analysis of eight representative genes broadly confirmed their RNA-seq profiles. Weighted gene co-expression network analysis identified 38 genes tightly co-expressed with <i>ZjbZIP7</i>, including the ethylene biosynthesis gene <i>ZjACO1</i>. A yeast one-hybrid assay further demonstrated that ZjbZIP7 bound to the <i>ZjACO1</i> promoter in yeast. <b>Conclusions:</b> These findings enhance our understanding of the evolutionary relationships and developmental expression patterns of the <i>ZjbZIP</i> gene family as a whole and provide valuable candidate genes for elucidating fruit-ripening mechanisms that may be useful in improving fruit quality in winter jujube breeding.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Blood Lipid Traits with Cognitive-Related Outcomes and Their Sensitivity to APOE-Region Instrumental Variables: A Mendelian Randomization and Colocalization Study.","authors":"Xiaoya Tian, Xiaolin Xue","doi":"10.3390/genes17101218","DOIUrl":"https://doi.org/10.3390/genes17101218","url":null,"abstract":"<p><p><b>Background:</b> Neurodegenerative, cognitive, and cerebrovascular outcomes are central to brain health. Previous studies have linked blood lipid traits to these outcomes, but associations differ across lipid components and outcome types. However, the contribution of APOE remains unclear. We compared these patterns, quantified their dependence on APOE, and identified shared signals outside the region. <b>Methods:</b> We used two-sample Mendelian randomization to examine associations between four blood lipid traits from the Global Lipids Genetics Consortium and seven cognitive-related outcomes from FinnGen R11, followed by regional colocalization analysis. We stratified instruments into APOE and non-APOE regions and compared region-specific estimates. Robust non-APOE signals supported by colocalization were further assessed using UK Biobank BIG40 imaging-derived phenotypes. <b>Results:</b> Genetically predicted high-density lipoprotein cholesterol (HDL-C) was inversely associated with the FinnGen composite endpoint of stroke excluding SAH and with cerebrovascular sequelae. Total cholesterol (TC) was positively associated with Alzheimer disease (AD) and dementia.Colocalization supported shared regional signals for TC-AD near TSBP1/TSBP1-AS1, LDL-C-AD within the extended HLA region, and HDL-C-stroke excluding SAH near ILRUN. Estimates for AD, dementia, and memory loss were sensitive to APOE-region exclusion, whereas the HDL-C-stroke estimate was materially unchanged. In separate exploratory analyses of 13 BIG40 imaging phenotypes, HDL-C colocalized with left lateral and right medial orbitofrontal gray-white matter intensity contrast. <b>Conclusions:</b> Lipid-related genetic effects differ across brain outcomes. AD and dementia estimates were sensitive to APOE-region instruments, whereas the HDL-C-associated signal for the composite stroke endpoint persisted after their exclusion. Exploratory imaging results nominate orbitofrontal intensity contrast as an HDL-C correlate.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 10","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}