Genome Medicine最新文献

{"title":"Identification of pathological pathways centered on circRNA dysregulation in association with irreversible progression of Alzheimer's disease.","authors":"Feng Wang, Yangping Li, Huifeng Shen, Paula Martinez-Feduchi, Xingyu Ji, Peng Teng, Siddharth Krishnakumar, Jian Hu, Li Chen, Yue Feng, Bing Yao","doi":"10.1186/s13073-024-01404-6","DOIUrl":"10.1186/s13073-024-01404-6","url":null,"abstract":"<p><strong>Background: </strong>Circular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as \"memory molecules\" that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer's disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored.</p><p><strong>Methods: </strong>We combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes.</p><p><strong>Results: </strong>We discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in the 7-month 5xFAD cortex. CircGIGYF2 level in AD patients' cortices negatively correlated with dementia severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs), including the cleavage and polyadenylation factor 6 (CPSF6). Moreover, circGigyf2 downregulation in AD promoted silencing activities of its sponged miRNAs and enhanced polyadenylation site processing efficiency of CPSF6 targets. Furthermore, circGigyf2 depletion in a mouse neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated apoptotic responses upon insults, which strongly support the causative roles of circGigyf2 deficiency in AD neurodegeneration.</p><p><strong>Conclusions: </strong>Together, our results unveiled brain circRNAs associated with irreversible disease progression in an AD mouse model that is also affected in AD patients and identified novel molecular mechanisms underlying the dysregulation of conserved circRNA pathways contributing to AD pathogenesis.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"129"},"PeriodicalIF":10.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KleTy: integrated typing scheme for core genome and plasmids reveals repeated emergence of multi-drug resistant epidemic lineages in Klebsiella worldwide.","authors":"Heng Li, Xiao Liu, Shengkai Li, Jie Rong, Shichang Xie, Yuan Gao, Ling Zhong, Quangui Jiang, Guilai Jiang, Yi Ren, Wanping Sun, Yuzhi Hong, Zhemin Zhou","doi":"10.1186/s13073-024-01399-0","DOIUrl":"10.1186/s13073-024-01399-0","url":null,"abstract":"<p><strong>Background: </strong>Clinically important lineages in Klebsiella, especially those expressing multi-drug resistance (MDR), pose severe threats to public health worldwide. They arose from the co-evolution of the vertically inherited core genome and horizontal gene transfers by plasmids, which has not been systematically explored.</p><p><strong>Methods: </strong>We designed KleTy, which consists of dedicated typing schemes for both the core genome and plasmids in Klebsiella. We compared the performance of KleTy with many state-of-the-art pipelines using both simulated and real data.</p><p><strong>Results: </strong>Employing KleTy, we genotyped 33,272 Klebsiella genomes, categorizing them into 1773 distinct populations and predicting the presence of 87,410 plasmids from 837 clusters (PCs). Notably, Klebsiella is the center of the plasmid-exchange network within Enterobacteriaceae. Our results associated the international emergence of prevalent Klebsiella populations with only four carbapenem-resistance (CR) PCs, two hypervirulent PCs, and two hvCR-PCs encoding both carbapenemase and hypervirulence. Furthermore, we observed the ongoing international emergence of bla_NDM, accompanied by the replacement of the previously dominant population, bla_KPC-encoding HC1360_8 (CC258), during 2003-2018, with the emerging bla_NDM-encoding HC1360_3 (CC147) thereafter. Additionally, expansions of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hvCRKP) were evidenced in both populations, driven by plasmids of MDR-hypervirulence convergences.</p><p><strong>Conclusions: </strong>The study illuminates how the global genetic landscape of Klebsiella has been shaped by the co-evolution of both the core genome and the plasmids, underscoring the importance of surveillance and control of the dissemination of plasmids for curtailing the emergence of hvCRKPs.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"130"},"PeriodicalIF":10.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11556198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring multi-omics and clinical characteristics linked to accelerated biological aging in Asian women of reproductive age: insights from the S-PRESTO study.","authors":"Li Chen, Karen Mei-Ling Tan, Jia Xu, Priti Mishra, Sartaj Ahmad Mir, Min Gong, Kothandaraman Narasimhan, Bryan Ng, Jun Shi Lai, Mya Thway Tint, Shirong Cai, Suresh Anand Sadananthan, Navin Michael, Jadegoud Yaligar, Sambasivam Sendhil Velan, Melvin Khee Shing Leow, Kok Hian Tan, Jerry Chan, Michael J Meaney, Shiao-Yng Chan, Yap Seng Chong, Johan G Eriksson","doi":"10.1186/s13073-024-01403-7","DOIUrl":"10.1186/s13073-024-01403-7","url":null,"abstract":"<p><strong>Background: </strong>Phenotypic age (PhenoAge), a widely used marker of biological aging, has been shown to be a robust predictor of all-cause mortality and morbidity in different populations. Existing studies on biological aging have primarily focused on individual domains, resulting in a lack of a comprehensive understanding of the multi-systemic dysregulation that occurs in aging.</p><p><strong>Methods: </strong>PhenoAge was evaluated based on a linear combination of chronological age (CA) and 9 clinical biomarkers in 952 multi-ethnic Asian women of reproductive age. Phenotypic age acceleration (PhenoAgeAccel), an aging biomarker, represents PhenoAge after adjusting for CA. This study conducts an in-depth association analysis of PhenoAgeAccel with clinical, nutritional, lipidomic, gut microbiome, and genetic factors.</p><p><strong>Results: </strong>Higher adiposity, glycaemia, plasma saturated fatty acids, kynurenine pathway metabolites, GlycA, riboflavin, nicotinamide, and insulin-like growth factor binding proteins were positively associated with PhenoAgeAccel. Conversely, a healthier diet and higher levels of pyridoxal phosphate, all-trans retinol, betaine, tryptophan, glutamine, histidine, apolipoprotein B, and insulin-like growth factors were inversely associated with PhenoAgeAccel. Lipidomic analysis found 132 lipid species linked to PhenoAgeAccel, with PC(O-36:0) showing the strongest positive association and CE(24:5) demonstrating the strongest inverse association. A genome-wide association study identified rs9864994 as the top genetic variant (P = 5.69E-07) from the ZDHHC19 gene. Gut microbiome analysis revealed that Erysipelotrichaceae UCG-003 and Bacteroides vulgatus were inversely associated with PhenoAgeAccel. Integrative network analysis of aging-related factors underscored the intricate links among clinical, nutritional and lipidomic variables, such as positive associations between kynurenine pathway metabolites, amino acids, adiposity, and insulin resistance. Furthermore, potential mediation effects of blood biomarkers related to inflammation, immune response, and nutritional and energy metabolism were observed in the associations of diet, adiposity, genetic variants, and gut microbial species with PhenoAgeAccel.</p><p><strong>Conclusions: </strong>Our findings provide a comprehensive analysis of aging-related factors across multiple platforms, delineating their complex interconnections. This study is the first to report novel signatures in lipidomics, gut microbiome and blood biomarkers specifically associated with PhenoAgeAccel. These insights are invaluable in understanding the molecular and metabolic mechanisms underlying biological aging and shed light on potential interventions to mitigate accelerated biological aging by targeting modifiable factors.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"128"},"PeriodicalIF":10.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curating genomic disease-gene relationships with Gene2Phenotype (G2P).","authors":"T Michael Yates, Morad Ansari, Louise Thompson, Sarah E Hunt, Elena Cibrian Uhalte, Rachel J Hobson, Joseph A Marsh, Caroline F Wright, Helen V Firth","doi":"10.1186/s13073-024-01398-1","DOIUrl":"10.1186/s13073-024-01398-1","url":null,"abstract":"<p><p>Genetically determined disorders are highly heterogenous in clinical presentation and underlying molecular mechanism. The evidence underpinning these conditions in the peer-reviewed literature requires robust critical evaluation for diagnostic use. Here, we present a structured curation process for Gene2Phenotype (G2P). This draws on multiple lines of clinical, bioinformatic and functional evidence. The process utilises and extends existing terminologies, allows for precise definition of the molecular basis of disease, and confidence levels to be attributed to a given gene-disease assertion. In-depth disease curation using this process will prove useful in applications including in diagnostics, research and development of targeted therapeutics. G2P: www.ebi.ac.uk/gene2phenotype .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"127"},"PeriodicalIF":10.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circular RNA landscape in extracellular vesicles from human biofluids.","authors":"Jingjing Zhao, Qiaojuan Li, Jia Hu, Hongwu Yu, Youmin Shen, Hongyan Lai, Qin Li, Hena Zhang, Yan Li, Zhuting Fang, Shenglin Huang","doi":"10.1186/s13073-024-01400-w","DOIUrl":"10.1186/s13073-024-01400-w","url":null,"abstract":"<p><strong>Background: </strong>Circular RNAs (circRNAs) have emerged as a prominent class of covalently closed single-stranded RNA molecules that exhibit tissue-specific expression and potential as biomarkers in extracellular vesicles (EVs) derived from liquid biopsies. Still, their characteristics and applications in EVs remain to be unveiled.</p><p><strong>Methods: </strong>We performed a comprehensive analysis of EV-derived circRNAs (EV-circRNAs) using transcriptomics data obtained from 1082 human body fluids, including plasma, urine, cerebrospinal fluid (CSF), and bile. Our validation strategy utilized RT-qPCR and RNA immunoprecipitation assays, complemented by computational techniques for analyzing EV-circRNA features and RNA-binding protein interactions.</p><p><strong>Results: </strong>We identified 136,327 EV-circRNAs from various human body fluids. Significantly, a considerable amount of circRNAs with a high back-splicing ratio are highly enriched in EVs compared to linear RNAs. Additionally, we discovered brain-specific circRNAs enriched in plasma EVs and cancer-associated EV-circRNAs linked to clinical outcomes. Moreover, we demonstrated that EV-circRNAs have the potential to serve as biomarkers for evaluating immunotherapy efficacy in non-small cell lung cancer (NSCLC). Importantly, we identified the involvement of RBPs, particularly YBX1, in the sorting mechanism of circRNAs into EVs.</p><p><strong>Conclusions: </strong>This study unveils the extensive repertoire of EV-circRNAs across human biofluids, offering insights into their potential as disease biomarkers and their mechanistic roles within EVs. The identification of specific circRNAs and the elucidation of RBP-mediated sorting mechanisms open new avenues for the clinical application of EV-circRNAs in disease diagnostics and therapeutics.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"126"},"PeriodicalIF":10.4,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiomyopathies in 100,000 genomes project: interval evaluation improves diagnostic yield and informs strategies for ongoing gene discovery.","authors":"Katherine S Josephs, Eleanor G Seaby, Philippa May, Pantazis Theotokis, Jing Yu, Avgi Andreou, Hannah Sinclair, Deborah Morris-Rosendahl, Ellen R A Thomas, Sarah Ennis, Angharad M Roberts, James S Ware","doi":"10.1186/s13073-024-01390-9","DOIUrl":"10.1186/s13073-024-01390-9","url":null,"abstract":"<p><strong>Background: </strong>Cardiomyopathies are clinically important conditions, with a strong genetic component. National genomic initiatives such as 100,000 Genome Project (100KGP) provide opportunity to study these rare conditions at scale beyond conventional research studies.</p><p><strong>Methods: </strong>We present the clinical and molecular characteristics of the 100KGP cohort, comparing paediatric and adult probands with diverse cardiomyopathies. We assessed the diagnostic yield and spectrum of genetic aetiologies across clinical presentations. We re-analysed existing genomic data using an updated analytical strategy (revised gene panels; unbiased analyses of de novo variants; and improved variant prioritisation strategies) to identify new causative variants in genetically unsolved children.</p><p><strong>Results: </strong>We identified 1918 individuals (1563 probands, 355 relatives) with cardiomyopathy (CM) in 100KGP. Probands, comprising 273 children and 1290 adults, were enrolled under > 55 different recruitment categories. Paediatric probands had higher rates of co-existing congenital heart disease (12%) compared to adults (0.9%). Diagnostic yield following 100KGP's initial analysis was significantly higher for children (19%) than for adults (11%) with 11% of diagnoses overall made in genes not on the existing UK paediatric or syndromic CM panel. Our re-analysis of paediatric probands yields a potential diagnosis in 40%, identifying new probable or possible diagnoses in 49 previously unsolved paediatric cases. Structural and intronic variants accounted for 11% of all potential diagnoses in children while de novo variants were identified in 17%.</p><p><strong>Conclusions: </strong>100KGP demonstrates the benefit of genome sequencing over a standalone panel in CM. Re-analysis of paediatric CM probands allowed a significant uplift in diagnostic yield, emphasising the importance of iterative re-evaluation in genomic studies. Despite these efforts, many children with CM remain without a genetic diagnosis, highlighting the need for better gene-disease relationship curation and ongoing data sharing. The 100KGP CM cohort is likely to be useful for further gene discovery, but heterogeneous ascertainment and key technical limitations must be understood and addressed.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"125"},"PeriodicalIF":10.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental-status-aware transcriptional decomposition establishes a cell state panorama of human cancers.","authors":"Yikai Luo, Han Liang","doi":"10.1186/s13073-024-01393-6","DOIUrl":"10.1186/s13073-024-01393-6","url":null,"abstract":"<p><strong>Background: </strong>Cancer cells evolve under unique functional adaptations that unlock transcriptional programs embedded in adult stem and progenitor-like cells for progression, metastasis, and therapeutic resistance. However, it remains challenging to quantify the stemness-aware cell state of a tumor based on its gene expression profile.</p><p><strong>Methods: </strong>We develop a developmental-status-aware transcriptional decomposition strategy using single-cell RNA-sequencing-derived tissue-specific fetal and adult cell signatures as anchors. We apply our method to various biological contexts, including developing human organs, adult human tissues, experimentally induced differentiation cultures, and bulk human tumors, to benchmark its performance and to reveal novel biology of entangled developmental signaling in oncogenic processes.</p><p><strong>Results: </strong>Our strategy successfully captures complex dynamics in developmental tissue bulks, reveals remarkable cellular heterogeneity in adult tissues, and resolves the ambiguity of cell identities in in vitro transformations. Applying it to large patient cohorts of bulk RNA-seq, we identify clinically relevant cell-of-origin patterns and observe that decomposed fetal cell signals significantly increase in tumors versus normal tissues and metastases versus primary tumors. Across cancer types, the inferred fetal-state strength outperforms published stemness indices in predicting patient survival and confers substantially improved predictive power for therapeutic responses.</p><p><strong>Conclusions: </strong>Our study not only provides a general approach to quantifying developmental-status-aware cell states of bulk samples but also constructs an information-rich, biologically interpretable, cell-state panorama of human cancers, enabling diverse translational applications.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"124"},"PeriodicalIF":10.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A genome-based survey of invasive pneumococci in Norway over four decades reveals lineage-specific responses to vaccination.","authors":"Vegard Eldholm, Magnus N Osnes, Martha L Bjørnstad, Daniel Straume, Rebecca A Gladstone","doi":"10.1186/s13073-024-01396-3","DOIUrl":"10.1186/s13073-024-01396-3","url":null,"abstract":"<p><strong>Background: </strong>Streptococcus pneumoniae is a major cause of mortality globally. The introduction of pneumococcal conjugate vaccines (PCVs) has reduced the incidence of the targeted serotypes significantly, but expansion of non-targeted serotypes, serotype replacement, and incomplete vaccine-targeting contribute to pneumococcal disease in the vaccine era. Here, we characterize the changing population genetic landscape of S. pneumoniae in Norway over a 41-year period (1982-2022).</p><p><strong>Methods: </strong>Since 2018, all cases of invasive pneumococcal disease have undergone whole-genome sequencing (WGS) at the Norwegian Institute of Public Health. In order to characterize the changing population over time, historical isolates were re-cultured and sequenced, resulting in a historical WGS dataset. Isolates were assigned to global pneumococcal sequence clusters (GPSCs) using PathogenWatch and assigned to serotypes using in silico (SeroBA) and in vitro methods (Quellung reaction). Temporal phylogenetic analyses were performed on GPSCs of particular interest.</p><p><strong>Results: </strong>The availability of WGS data allowed us to study capsular variation at the level of individual lineages. We detect highly divergent fates for different GPSCs following the introduction of PCVs. For two out of eight major GPSCs, we identified multiple instances of serotype switching from vaccine types to non-vaccine types. Dating analyses suggest that most instances of serotype switching predated the introduction of PCVs, but expansion occurred after their introduction. Furthermore, selection for penicillin non-susceptibility was not a driving force for the changing serotype distribution within the GPSCs over time.</p><p><strong>Conclusions: </strong>PCVs have been major shapers of the Norwegian disease-causing pneumococcal population, both at the level of serotype distributions and the underlying lineage dynamics. Overall, the introduction of PCVs has reduced the incidence of invasive disease. However, some GPSCs initially dominated by vaccine types escaped the effect of vaccination through expansion of non-vaccine serotypes. Close monitoring of circulating lineages and serotypes will be key for ensuring optimal vaccination coverage going forward.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"123"},"PeriodicalIF":10.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142498964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomic integration analysis identifies atherogenic metabolites mediating between novel immune genes and cardiovascular risk.","authors":"Robert Carreras-Torres, Iván Galván-Femenía, Xavier Farré, Beatriz Cortés, Virginia Díez-Obrero, Anna Carreras, Ferran Moratalla-Navarro, Susana Iraola-Guzmán, Natalia Blay, Mireia Obón-Santacana, Víctor Moreno, Rafael de Cid","doi":"10.1186/s13073-024-01397-2","DOIUrl":"10.1186/s13073-024-01397-2","url":null,"abstract":"<p><strong>Background: </strong>Understanding genetic-metabolite associations has translational implications for informing cardiovascular risk assessment. Interrogating functional genetic variants enhances our understanding of disease pathogenesis and the development and optimization of targeted interventions.</p><p><strong>Methods: </strong>In this study, a total of 187 plasma metabolite levels were profiled in 4974 individuals of European ancestry of the GCAT| Genomes for Life cohort. Results of genetic analyses were meta-analysed with additional datasets, resulting in up to approximately 40,000 European individuals. Results of meta-analyses were integrated with reference gene expression panels from 58 tissues and cell types to identify predicted gene expression associated with metabolite levels. This approach was also performed for cardiovascular outcomes in three independent large European studies (N = 700,000) to identify predicted gene expression additionally associated with cardiovascular risk. Finally, genetically informed mediation analysis was performed to infer causal mediation in the relationship between gene expression, metabolite levels and cardiovascular risk.</p><p><strong>Results: </strong>A total of 44 genetic loci were associated with 124 metabolites. Lead genetic variants included 11 non-synonymous variants. Predicted expression of 53 fine-mapped genes was associated with 108 metabolite levels; while predicted expression of 6 of these genes was also associated with cardiovascular outcomes, highlighting a new role for regulatory gene HCG27. Additionally, we found that atherogenic metabolite levels mediate the associations between gene expression and cardiovascular risk. Some of these genes showed stronger associations in immune tissues, providing further evidence of the role of immune cells in increasing cardiovascular risk.</p><p><strong>Conclusions: </strong>These findings propose new gene targets that could be potential candidates for drug development aimed at lowering the risk of cardiovascular events through the modulation of blood atherogenic metabolite levels.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"122"},"PeriodicalIF":10.4,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142498965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations.","authors":"Morag A Lewis, Maria Lachgar-Ruiz, Francesca Di Domenico, Graham Duddy, Jing Chen, Sergio Fernandez, Matias Morin, Gareth Williams, Miguel Angel Moreno Pelayo, Karen P Steel","doi":"10.1186/s13073-024-01394-5","DOIUrl":"10.1186/s13073-024-01394-5","url":null,"abstract":"<p><strong>Background: </strong>Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a post-transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in miR-96 all exhibit hearing impairment, in homozygosis if not in heterozygosis, but different mutations result in different physiological, structural and transcriptional phenotypes.</p><p><strong>Methods: </strong>Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. We have carried out auditory brainstem response tests to examine their hearing with age and after noise exposure and have used confocal and scanning electron microscopy to examine the ultrastructure of the organ of Corti and hair cell synapses. Bulk RNA-seq was carried out on the organs of Corti of postnatal mice, followed by bioinformatic analyses to identify candidate targets.</p><p><strong>Results: </strong>While mice homozygous for either mutation are profoundly deaf from 2 weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice.</p><p><strong>Conclusions: </strong>Our work adds further support for the importance of the gain of novel targets in microRNA mutants and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"121"},"PeriodicalIF":10.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}