Nature genetics最新文献

{"title":"Using large-scale population-based data to improve disease risk assessment of clinical variants","authors":"Iain S. Forrest, Kuan-Lin Huang, Julie M. Eggington, Wendy K. Chung, Daniel M. Jordan, Ron Do","doi":"10.1038/s41588-025-02212-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02212-3","url":null,"abstract":"<p>Understanding the disease risk of genetic variants is fundamental to precision medicine. Estimates of penetrance—the probability of disease for individuals with a variant allele—rely on disease-specific cohorts, clinical testing and emerging electronic health record (EHR)-linked biobanks. These data sources, while valuable, each have limitations in quality, representativeness and analyzability. Here, we provide a historical account of the currently accepted pathogenicity classification system and data available in ClinVar, a public archive that aggregates variant interpretations but lacks detailed data for accurate penetrance assessment, highlighting its oversimplification of disease risk. We propose an integrative Bayesian framework that unifies pathogenicity and penetrance, leveraging both functional and real-world evidence to refine risk predictions. In addition, we advocate for enhancing ClinVar with the inclusion of high-priority phenotypes, age-stratified data and population-based cohorts linked to EHRs. We suggest developing a community repository of population-based penetrance estimates to support the clinical application of genetic data.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340982","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":"Incorporating genetic data improves target trial emulations and informs the use of polygenic scores in randomized controlled trial design","authors":"Jakob German, Zhiyu Yang, Sarah Urbut, Pekka Vartiainen, Pradeep Natarajan, Elisabetta Pattorno, Zoltan Kutalik, Anthony Philippakis, Andrea Ganna","doi":"10.1038/s41588-025-02229-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02229-8","url":null,"abstract":"<p>Randomized controlled trials (RCTs) remain the gold standard for evaluating medical interventions, yet ethical, practical and financial constraints often necessitate reliance on observational data and trial emulations. This study explores how integrating genetic data can enhance both emulated and traditional trial designs. Using FinnGen (<i>n</i> = 425,483), we emulated four major cardiometabolic RCTs and showed how reduced differences in polygenic scores (PGS) between trial arms track improvement in study design. Simulation studies reveal that PGS alone cannot fully adjust for unmeasured confounding. Instead, Mendelian randomization analyses can be used to detect likely confounders. Finally, trial emulations provide a platform to assess and refine PGS implementation for genetic enrichment strategies. By comparing associations of PGS with trial outcomes in the general population and emulated trial cohorts, we highlight the need to validate prognostic enrichment approaches in trial-relevant populations. These results highlight the growing potential of incorporating genetic information to optimize clinical trial design.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"43 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311730","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":"Transferability of European-derived Alzheimer’s disease polygenic risk scores across multiancestry populations","authors":"Aude Nicolas, Richard Sherva, Benjamin Grenier-Boley, Yoontae Kim, Masataka Kikuchi, Jigyasha Timsina, Itziar de Rojas, María Carolina Dalmasso, Xiaopu Zhou, Yann Le Guen, Carlos E. Arboleda-Bustos, Maria Aparecida Camargos Bicalho, Maëlenn Guerchet, Sven van der Lee, Monica Goss, Atahualpa Castillo, Céline Bellenguez, Fahri Küçükali, Claudia L. Satizabal, Bernard Fongang, Qiong Yang, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina-Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J. Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Han Cao, Nancy Y. Ip, Amy K. Y. Fu, Fanny C. F. Ip, Natividad Olivar, Carolina Muchnik, Carolina Cuesta, Lorenzo Campanelli, Patricia Solis, Daniel Gustavo Politis, Silvia Kochen, Luis Ignacio Brusco, Mercè Boada, Pablo García-González, Raquel Puerta, Pablo Mir, Luis M. Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Jose Luís Royo, Eloy Rodriguez-Rodriguez, Hilkka Soininen, Sami Heikkinen, Alexandre de Mendonça, Shima Mehrabian, Latchezar Traykov, Jakub Hort, Martin Vyhnalek, Katrine Laura Rasmussen, Jesper Qvist Thomassen, Yolande A. L. Pijnenburg, Henne Holstege, John C. van Swieten, Harro Seelaar, Jurgen A. H. R. Claassen, Willemijn J. Jansen, Inez Ramakers, Frans Verhey, Aad van der Lugt, Philip Scheltens, Jenny Ortega-Rojas, Ana Gabriela Concha Mera, Maria F. Mahecha, Rodrigo Pardo, Gonzalo Arboleda, Shahram Bahrami, Vera Fominykh, Geir Selbæk, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Anne Boland, Jean-François Deleuze, Luiz Armando de Marco, Edgar Nunes de Moraes, Bernardo de Mattos Viana, Marco Túlio Gualberto Cintra, Teresa Juarez-Cedillo, Anthony J. Griswold, Tatiana Forund, Jonathan Haines, Lindsay Farrer, Anita DeStefano, Ellen Wijsman, Richard Mayeux, Margaret Pericak-Vance, Brian Kunkle, Alison Goate, Gerard D. Schellenberg, Badri Vardarajan, Li-San Wang, Yuk Yee Leung, Clifton L. Dalgard, Gael Nicolas, David Wallon, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Bárbara Angel, Sergio Gloger, Maria Victoria Chacon, Rafael Aranguiz, Paulina Orellana, Andrea Slachevsky, Christian Gonzalez-Billault, Cecilia Albala, Patricio Fuentes, Perminder Sachdev, Karen A. Mather, Richard L. Hauger, Victoria Merritt, Matthew Panizzon, Rui Zhang, J. Michael Gaziano, Roberta Ghidoni, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Benedetta Nacmias, Paolo Caffarra, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Fabrizio Piras, Hampton L. Leonard, Jenifer S. Yokoyama, Mike A. Nalls, Akinori Miyashita, Norikazu Hara, Kouichi Ozaki, Shumpei Niida, Julie Williams, Carlo Masullo, Philippe Amouyel, Pierre-Marie Preux, Pascal Mbelesso, Bébène Bandzouzi, Andy Saykin, Frank Jessen, Patrick G. Kehoe, Cornelia Van Duijn, Nesrine Ben Salem, Ruth Frikke-Schmidt, Lotfi Cherni, Michael D. Greicius, Magda Tsolaki, Pascual Sánchez-Juan, Marco Aurélio Romano Silva, Tenielle Porter, Simon M. Laws, Kristel Sleegers, Martin Ingelsson, Jean-François Dartigues, Sudha Seshadri, Giacomina Rossi, Laura Morelli, Mikko Hiltunen, Rebecca Sims, Wiesje van der Flier, Ole A. Andreassen, Humberto Arboleda, Carlos Cruchaga, Valentina Escott-Price, Agustín Ruiz, Kun Ho Lee, Takeshi Ikeuchi, Alfredo Ramirez, Jungsoo Gim, Mark Logue, Jean-Charles Lambert","doi":"10.1038/s41588-025-02227-w","DOIUrl":"https://doi.org/10.1038/s41588-025-02227-w","url":null,"abstract":"<p>A polygenic score (PGS) for Alzheimer’s disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (<i>APOE</i>). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the <i>APOE</i> region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"23 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311724","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":"Author Correction: A likelihood-based framework for demographic inference from genealogical trees","authors":"Caoqi Fan, Jordan L. Cahoon, Bryan L. Dinh, Diego Ortega-Del Vecchyo, Christian D. Huber, Michael D. Edge, Nicholas Mancuso, Charleston W. K. Chiang","doi":"10.1038/s41588-025-02257-4","DOIUrl":"https://doi.org/10.1038/s41588-025-02257-4","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-025-02129-x, published online 20 March 2025.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"21 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304540","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":"Publisher Correction: GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia","authors":"Lincoln M. P. Shade, Yuriko Katsumata, Erin L. Abner, Khine Zin Aung, Steven A. Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Timothy J. Hohman, Shubhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Walter A. Kukull, Kwangsik Nho, Andrew J. Saykin, David A. Bennett, Julie A. Schneider, Mark T. W. Ebbert, Peter T. Nelson, David W. Fardo","doi":"10.1038/s41588-024-02046-5","DOIUrl":"https://doi.org/10.1038/s41588-024-02046-5","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-024-01939-9, published online 8 October 2024.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"183 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311726","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":"Author Correction: GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia","authors":"Lincoln M. P. Shade, Yuriko Katsumata, Erin L. Abner, Khine Zin Aung, Steven A. Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Timothy J. Hohman, Shubhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Walter A. Kukull, Kwangsik Nho, Andrew J. Saykin, David A. Bennett, Julie A. Schneider, Mark T. W. Ebbert, Peter T. Nelson, David W. Fardo","doi":"10.1038/s41588-024-02045-6","DOIUrl":"https://doi.org/10.1038/s41588-024-02045-6","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-024-01939-9, published online 8 October 2024.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"8 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311727","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":"A scalable gut epithelial organoid model reveals the genome-wide colonization landscape of a human-adapted pathogen","authors":"Maria Letizia Di Martino, Laura Jenniches, Anjeela Bhetwal, Jens Eriksson, Ana C. C. Lopes, Angelika Ntokaki, Martina Pasqua, Magnus Sundbom, Martin Skogar, Wilhelm Graf, Dominic-Luc Webb, Per M. Hellström, André Mateus, Lars Barquist, Mikael E. Sellin","doi":"10.1038/s41588-025-02218-x","DOIUrl":"https://doi.org/10.1038/s41588-025-02218-x","url":null,"abstract":"<p>Studying the pathogenesis of human-adapted microorganisms is challenging, since small animal models often fail to recapitulate human physiology. Hence, the comprehensive genetic and regulatory circuits driving the infection process of principal human pathogens such as <i>Shigella flexneri</i> remain to be defined. We combined large-scale <i>Shigella</i> infections of enteroids and colonoids with transposon-directed insertion sequencing and Bayesian statistical modeling to address infection bottlenecks, thereby establishing the comprehensive genome-wide map of <i>Shigella</i> genes required to infect human intestinal epithelium. This revealed the <i>Shigella</i> virulence effectors essential for epithelial cell colonization across geometries and intestinal segments, identified over 100 chromosomal genes involved in the process and uncovered a post-transcriptional mechanism whereby tRNA-modification enzymes and differential codon usage exert global control of a bacterial virulence program. Our findings provide a broadly applicable framework for combining advanced organotypic tissue culture with functional genomics and computational tools to map human–microorganism interactions at scale.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"6 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268608","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":"Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance","authors":"Elizabeth Dorans, Karthik Jagadeesh, Kushal Dey, Alkes L. Price","doi":"10.1038/s41588-025-02220-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02220-3","url":null,"abstract":"<p>Methods that analyze single-cell paired RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) multiome data have shown promise in linking regulatory elements to genes. However, existing methods exhibit low concordance and do not capture the effects of genomic distance. We propose pgBoost, an integrative modeling framework that trains a non-linear combination of existing linking strategies (including genomic distance) on expression quantitative trait locus (eQTL) data to assign a probabilistic score to each candidate single-nucleotide polymorphism–gene link. pgBoost attained higher enrichment than existing methods for evaluation sets derived from eQTL, activity-by-contact, CRISPR and genome-wide association study (GWAS) data. We further determined that restricting pgBoost to features from a focal cell type improved power to identify links relevant to that cell type. We highlight several examples in which pgBoost linked fine-mapped GWAS variants to experimentally validated or biologically plausible target genes that were not implicated by other methods. In conclusion, a non-linear combination of linking strategies improves power to identify target genes underlying GWAS associations.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"9 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268609","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":"Organoid models advance dysentery control","authors":"Sydney L. Miles, Serge Mostowy","doi":"10.1038/s41588-025-02219-w","DOIUrl":"https://doi.org/10.1038/s41588-025-02219-w","url":null,"abstract":"Shigella is a major human pathogen with a stark lack of pipelines linking genome content to clinical pathogenesis. An innovative study using large-scale organoid models, combined with genome-wide mutagenesis screening, reveals virulence factors required for Shigella colonization.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"41 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268651","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":"In vivo epigenome editing with NovaIscB","authors":"Wei Li","doi":"10.1038/s41588-025-02243-w","DOIUrl":"10.1038/s41588-025-02243-w","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1325-1325"},"PeriodicalIF":31.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269048","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}