Nature genetics最新文献

{"title":"A contextual genomic perspective on physical activity and its relationship to health, well being and illness","authors":"Marco Galimberti, Daniel F. Levey, Joseph D. Deak, Keyrun Adhikari, Cassie Overstreet, Priya Gupta, Rachana Nitin, Hang Zhou, Nicole J. Lake, Kelly M. Harrington, Luc Djousse, Lea K. Davis, VA Million Veteran Program, J. Michael Gaziano, Murray B. Stein, Joel Gelernter","doi":"10.1038/s41588-025-02260-9","DOIUrl":"10.1038/s41588-025-02260-9","url":null,"abstract":"Physical activity (PA) is one of the most fundamental traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program, we conducted genetic analyses of leisure, work and home-time PA. For leisure, we included 189,812 individuals of European ancestry (SNP-based heritability (h2) = 0.083 ± 0.005), 27,044 of African ancestry (h2 = 0.034 ± 0.017) and 10,263 of Latin American ancestry (h2 = 0.083 ± 0.036) in a cross-ancestry meta-analysis with UK Biobank data, identifying 70 lead variants. Leisure-time PA was genetically distinct from PA at home or work, with the latter two showing less health benefit with respect to health outcomes and lifespan. Mendelian randomization analyses showed a protective role of leisure-time PA against COVID-19 hospitalization (β = −0.067 ± 0.016; P = 2.8 × 10−5), and with other traits including cardiovascular and respiratory system diseases, metabolic traits and aging. These findings provide new insights into the biology of PA, showing specific causal health benefits of leisure-time PA. Genome-wide association meta-analyses of leisure, work and home-time physical activity (PA) from European, African and Latin American ancestries provide insights into the biology of PA and its relationship to health and diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1860-1871"},"PeriodicalIF":29.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02260-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669927","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":"Improved multiancestry fine-mapping identifies cis-regulatory variants underlying molecular traits and disease risk","authors":"Zeyun Lu, Xinran Wang, Matthew Carr, Artem Kim, Steven Gazal, Pejman Mohammadi, Lang Wu, James Pirruccello, Linda Kachuri, Alexander Gusev, Nicholas Mancuso","doi":"10.1038/s41588-025-02262-7","DOIUrl":"10.1038/s41588-025-02262-7","url":null,"abstract":"Multiancestry statistical fine-mapping of cis-molecular quantitative trait loci (cis-molQTL) aims to improve the precision of distinguishing causal cis-molQTLs from tagging variants. Here we present the sum of shared single effects (SuShiE) model, which leverages linkage disequilibrium heterogeneity to improve fine-mapping precision, infer cross-ancestry effect size correlations and estimate ancestry-specific expression prediction weights. Through extensive simulations, we find that SuShiE consistently outperforms existing methods. We apply SuShiE to 36,907 molecular phenotypes including mRNA expression and protein levels from individuals of diverse ancestries in the TOPMed-MESA and GENOA studies. SuShiE fine-maps cis-molQTLs for 18.2% more genes compared with existing methods while prioritizing fewer variants and exhibiting greater functional enrichment. While SuShiE infers highly consistent cis-molQTL architectures across ancestries, it finds evidence of heterogeneity at genes with predicted loss-of-function intolerance. Lastly, using SuShiE-derived cis-molQTL effect sizes, we perform transcriptome- and proteome-wide association studies on six white blood cell-related traits in the All of Us biobank and identify 25.4% more genes compared with existing methods. Overall, SuShiE provides new insights into the cis-genetic architecture of molecular traits. SuShiE is a multiancestry fine-mapping method for molecular quantitative trait loci that leverages linkage disequilibrium heterogeneity to improve resolution, infer cross-ancestry effect size correlations and estimate ancestry-specific expression prediction weights.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1881-1889"},"PeriodicalIF":29.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NKX2-1 drives neuroendocrine transdifferentiation of prostate cancer via epigenetic and 3D chromatin remodeling","authors":"Xiaodong Lu, Viriya Keo, Irina Cheng, Wanqing Xie, Galina Gritsina, Juan Wang, Lina Lu, Cheng-Kai Shiau, Yueying He, Qiushi Jin, Peng Jin, Martin G. Sanda, Victor G. Corces, Nicolas Altemose, Ruli Gao, Jonathan C. Zhao, Jindan Yu","doi":"10.1038/s41588-025-02265-4","DOIUrl":"10.1038/s41588-025-02265-4","url":null,"abstract":"A substantial amount of castration-resistant prostate cancer (CRPC) progresses into a neuroendocrine (NE) subtype, known as NEPC, which is associated with poor clinical outcomes. Here we report distinct three-dimensional chromatin architectures between NEPC and CRPC tumors, which were recapitulated by isogenic cell lines undergoing NE transformation (NET). Mechanistically, pioneer factors such as FOXA2 initiate binding at NE enhancers to mediate regional DNA demethylation and induce neural transcription factor (TF) NKX2-1 expression. NKX2-1 preferentially binds gene promoters and interacts with enhancer-bound FOXA2 through chromatin looping. NKX2-1 is highly expressed in NEPC and indispensable for NET of prostate cancer. NKX2-1/FOXA2 further recruits p300/CBP to activate NE enhancers, and pharmacological inhibition of p300/CBP effectively blunts NE gene expression and abolishes NEPC tumor growth. Taken together, our study reports a hierarchical network of TFs governed by NKX2-1 in critically regulating chromatin remodeling and driving luminal-to-NE transformation and suggests promising therapeutic approaches to mitigate NEPC. Single-cell RNA and assay for transposase-accessible chromatin sequencing in isogenic prostate adenocarcinoma cells undergoing neuroendocrine transition identify dynamic changes in chromatin and transcriptomic states coregulated by NKX2-1, FOXA2 and p300/CBP.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1966-1980"},"PeriodicalIF":29.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02265-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669922","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":"Therapeutic strategies for fragile X syndrome and implications for other gene-silencing disorders","authors":"Aseel Gadban, Keith M. Gunapala, Verdon Taylor, Nissim Benvenisty","doi":"10.1038/s41588-025-02255-6","DOIUrl":"10.1038/s41588-025-02255-6","url":null,"abstract":"Gene-silencing disorders, of which fragile X syndrome (FXS) is the most prevalent, are diseases caused by a blockade of gene transcription, usually due to DNA hypermethylation. FXS is a common form of inherited intellectual disability and autism. Unlike most hereditary diseases driven by mutations within the protein-coding region of a gene, FXS is caused by a trinucleotide expansion in the 5′-untranslated region of the FMR1 gene, leading to hypermethylation and transcriptional silencing. Modeling FXS with human pluripotent stem cells offers a clinically relevant platform to study disease mechanisms and explore potential therapies through reactivating FMR1 expression by genetic and epigenetic means or through drug screening. This Perspective reviews the various cellular models and therapeutic strategies proposed over the past decade, highlighting their potential to advance the treatment of FXS. We also discuss the benefits and challenges of gene activation therapies, drawing comparisons with other gene-silencing disorders, including imprinting diseases and X-linked disorders. This Perspective discusses therapeutic strategies to reactivate the silenced gene in fragile X syndrome by genetic and epigenetic means and drug screening and their relevance for other gene-silencing diseases, such as imprinting or X-linked disorders.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1812-1822"},"PeriodicalIF":29.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward improving multiomic research in understudied cereals","authors":"Fanjing Yang, Xiaojiao Gong, Pan Zhao, Lingtong Cheng, Yujie Zhang, Yingting Luo, Qian-Hao Zhu, Chu-Yu Ye","doi":"10.1038/s41588-025-02245-8","DOIUrl":"10.1038/s41588-025-02245-8","url":null,"abstract":"With the looming challenges of climate change and population pressure, understudied cereals hold notably untapped potential for future global food security and sustainable agriculture due to their unique nutritional profiles and notable stress resilience. Multiomics holds great promise in realizing the value of understudied cereals by understanding the genetic basis and molecular mechanisms regulating their unique traits; however, multiomic studies of understudied cereals still lag behind those of major cereals, hindering their genetic improvement and wide adoption in modern agriculture. Here, we discuss the limitations and challenges in multiomic studies of understudied cereals and how they can be overcome to enhance utilization of the traits unique to understudied cereals in improving both themselves and major cereals. We also offer a database specific to understudied cereals, including multiomics data from 12 understudied cereals and wild relatives for some of these, to serve the community. Understudied cereals offer untapped potential for food security, yet multiomic research substantially lags behind that of major cereals. This Perspective discusses these challenges and introduces a dedicated database to serve the community.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2106-2115"},"PeriodicalIF":29.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy","authors":"Jie Liu, Duc Tran, Liying Xue, Brian J. Wiley, Caitlyn Vlasschaert, Caroline J. Watson, Hamish A. J. MacGregor, Xiaoyu Zong, Irenaeus C. C. Chan, Indraniel Das, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Benjamin L. Ebert, Taralynn Mack, Yash Pershad, Brian Sharber, Michael Berger, Ahmet Zehir, Ryan Ptashkin, Ross L. Levine, Elli Papaemmanuil, Vijai Joseph, Teng Gao, Yelena Kemel, Diana Mandelker, Konrad H. Stopsack, Paul D. P. Pharoah, Semanti Mukherjee, Li Ding, Yin Cao, Matthew J. Walter, Jamie R. Blundell, Nilanjan Chatterjee, Kenneth Offit, Lucy A. Godley, Daniel C. Link, Zsofia K. Stadler, Alexander G. Bick, Pradeep Natarajan, Kelly L. Bolton","doi":"10.1038/s41588-025-02250-x","DOIUrl":"10.1038/s41588-025-02250-x","url":null,"abstract":"With age, clonal expansions occur pervasively across normal tissues yet only in rare instances lead to cancer, despite being driven by well-established cancer drivers. Characterization of the factors that influence clonal progression is needed to inform interventional approaches. Germline genetic variation influences cancer risk and shapes tumor mutational profile, but its influence on the mutational landscape of normal tissues is not well known. Here we studied the impact of germline genetic variation on clonal hematopoiesis (CH) in 731,835 individuals. We identified 22 new CH-predisposition genes, most of which predispose to CH driven by specific mutational events. CH-predisposition genes contribute to unique somatic landscapes, reflecting the influence of germline genetic backdrop on gene-specific CH fitness. Correspondingly, somatic–germline interactions influence the risk of CH progression to hematologic malignancies. These results demonstrate that germline genetic variation influences somatic evolution in the blood, findings that likely extend to other tissues. The relationship between pathogenic germline variation, clonal hematopoiesis (CH) and risk of hematologic malignancy is explored in 731,835 individuals across 6 cohorts. Carriers of variants in certain genes show distinct patterns of CH and increased risk of CH progression to malignancy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1872-1880"},"PeriodicalIF":29.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02250-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629584","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":"Enhancer mutational screen in vivo","authors":"Tiago Faial","doi":"10.1038/s41588-025-02277-0","DOIUrl":"10.1038/s41588-025-02277-0","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding in situ genome sequencing","authors":"Petra Gross","doi":"10.1038/s41588-025-02278-z","DOIUrl":"10.1038/s41588-025-02278-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Y chromosome loss in cancer","authors":"Safia Danovi","doi":"10.1038/s41588-025-02276-1","DOIUrl":"10.1038/s41588-025-02276-1","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perturb-Multimodal pooled screening in intact tissues","authors":"Wei Li","doi":"10.1038/s41588-025-02279-y","DOIUrl":"10.1038/s41588-025-02279-y","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}