Nature genetics最新文献

{"title":"Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1","authors":"Thomas R. W. Oliver, Andrew R. J. Lawson, Henry Lee-Six, Anna Tollit, Hyunchul Jung, Yvette Hooks, Rashesh Sanghvi, Matthew D. Young, Timothy M. Butler, Pantelis A. Nicola, Taryn D. Treger, Stefanie V. Lensing, G. A. Amos Burke, Kristian Aquilina, Ulrike Löbel, Isidro Cortes-Ciriano, Darren Hargrave, Mette Jorgensen, Flora A. Jessop, Tim H. H. Coorens, Adrienne M. Flanagan, Kieren Allinson, Inigo Martincorena, Thomas S. Jacques, Sam Behjati","doi":"10.1038/s41588-025-02097-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02097-2","url":null,"abstract":"<p>Cancer predisposition syndromes mediated by recessive cancer genes generate tumors via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here we performed whole-genome and whole-exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multisystem cancer-predisposing syndrome mediated by constitutive monoallelic <i>NF1</i> inactivation. We identified multiple independent <i>NF1</i> driver variants in histologically normal tissues, but not in 610 biopsies from two nonpredisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating <i>NF1</i> mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbor second hits in <i>NF1</i>, the extent and pattern of which may underpin the syndrome’s cancer phenotype.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"128 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485661","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":"Secure and federated genome-wide association studies for biobank-scale datasets","authors":"Hyunghoon Cho, David Froelicher, Jeffrey Chen, Manaswitha Edupalli, Apostolos Pyrgelis, Juan R. Troncoso-Pastoriza, Jean-Pierre Hubaux, Bonnie Berger","doi":"10.1038/s41588-025-02109-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02109-1","url":null,"abstract":"<p>Sharing data across institutions for genome-wide association studies (GWAS) would enhance the discovery of genetic variation linked to health and disease^1,2. However, existing data-sharing regulations limit the scope of such collaborations³. Although cryptographic tools for secure computation promise to enable collaborative analysis with formal privacy guarantees, existing approaches either are computationally impractical or do not implement current state-of-the-art methods^4,5,6. We introduce secure federated genome-wide association studies (SF-GWAS), a combination of secure computation frameworks and distributed algorithms that empowers efficient and accurate GWAS on private data held by multiple entities while ensuring data confidentiality. SF-GWAS supports widely used GWAS pipelines based on principal-component analysis or linear mixed models. We demonstrate the accuracy and practical runtimes of SF-GWAS on five datasets, including a UK Biobank cohort of 410,000 individuals, showcasing an order-of-magnitude improvement in runtime compared to previous methods. Our work enables secure collaborative genomic studies at unprecedented scale.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"14 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477726","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":"Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels","authors":"Gareth Hawkes, Kartik Chundru, Leigh Jackson, Kashyap A. Patel, Anna Murray, Andrew R. Wood, Caroline F. Wright, Michael N. Weedon, Timothy M. Frayling, Robin N. Beaumont","doi":"10.1038/s41588-025-02095-4","DOIUrl":"https://doi.org/10.1038/s41588-025-02095-4","url":null,"abstract":"<p>The contribution of rare noncoding genetic variation to common phenotypes is largely unknown, as a result of a historical lack of population-scale whole-genome sequencing data and the difficulty of categorizing noncoding variants into functionally similar groups. To begin addressing these challenges, we performed a <i>cis</i> association analysis using whole-genome sequencing data, consisting of 1.1 billion variants, 123 million noncoding aggregate-based tests and 2,907 circulating protein levels in ~50,000 UK Biobank participants. We identified 604 independent rare noncoding single-variant associations with circulating protein levels. Unlike protein-coding variation, rare noncoding genetic variation was almost as likely to increase or decrease protein levels. Rare noncoding aggregate testing identified 357 conditionally independent associated regions. Of these, 74 (21%) were not detectable by single-variant testing alone. Our findings have important implications for the identification, and role, of rare noncoding genetic variation associated with common human phenotypes, including the importance of testing aggregates of noncoding variants.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"24 3 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477723","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: Pangenome graphs and their applications in biodiversity genomics","authors":"Simona Secomandi, Guido Roberto Gallo, Riccardo Rossi, Carlos Rodríguez Fernandes, Erich D. Jarvis, Andrea Bonisoli-Alquati, Luca Gianfranceschi, Giulio Formenti","doi":"10.1038/s41588-025-02132-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02132-2","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-024-02029-6, published online 8 January 2025.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462170","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":"Safeguard repressor locks hepatocyte identity and blocks liver cancer","authors":"","doi":"10.1038/s41588-025-02082-9","DOIUrl":"https://doi.org/10.1038/s41588-025-02082-9","url":null,"abstract":"PROX1 acts as a molecular ‘cell fate guardian’ in hepatocytes, preserving liver cell identity throughout life by actively repressing unwanted plasticity. PROX1 loss impairs liver regeneration and fuels tumor formation, whereas PROX1 activation halts cancer formation and progression, revealing unexpected therapeutic potential.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"2 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443446","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":"Mass spectrometry-based mapping of plasma protein QTLs in children and adolescents","authors":"Yansheng Liu","doi":"10.1038/s41588-025-02088-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02088-3","url":null,"abstract":"Mass spectrometry-based proteomics demonstrated its increasing analytical power and unique strengths in measuring genome-wide plasma proteomes and identifying protein quantitative trait loci (pQTLs), as reported in a study of over 3,000 Danish children and adolescents.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"85 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443326","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":"Plasma proteome variation and its genetic determinants in children and adolescents","authors":"Lili Niu, Sara Elizabeth Stinson, Louise Aas Holm, Morten Asp Vonsild Lund, Cilius Esmann Fonvig, Leonardo Cobuccio, Jonas Meisner, Helene Bæk Juel, Joao Fadista, Maja Thiele, Aleksander Krag, Jens-Christian Holm, Simon Rasmussen, Torben Hansen, Matthias Mann","doi":"10.1038/s41588-025-02089-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02089-2","url":null,"abstract":"<p>Our current understanding of the determinants of plasma proteome variation during pediatric development remains incomplete. Here, we show that genetic variants, age, sex and body mass index significantly influence this variation. Using a streamlined and highly quantitative mass spectrometry-based proteomics workflow, we analyzed plasma from 2,147 children and adolescents, identifying 1,216 proteins after quality control. Notably, the levels of 70% of these were associated with at least one of the aforementioned factors, with protein levels also being predictive. Quantitative trait loci (QTLs) regulated at least one-third of the proteins; between a few percent and up to 30-fold. Together with excellent replication in an additional 1,000 children and 558 adults, this reveals substantial genetic effects on plasma protein levels, persisting from childhood into adulthood. Through Mendelian randomization and colocalization analyses, we identified 41 causal genes for 33 cardiometabolic traits, emphasizing the value of protein QTLs in drug target identification and disease understanding.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"13 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443448","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":"Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings","authors":"Sean L. Zheng, Sean J. Jurgens, Kathryn A. McGurk, Xiao Xu, Chris Grace, Pantazis I. Theotokis, Rachel J. Buchan, Catherine Francis, Antonio de Marvao, Lara Curran, Wenjia Bai, Chee Jian Pua, Hak Chiaw Tang, Paloma Jorda, Marjon A. van Slegtenhorst, Judith M. A. Verhagen, Andrew R. Harper, Elizabeth Ormondroyd, Calvin W. L. Chin, Antonis Pantazis, John Baksi, Brian P. Halliday, Paul Matthews, Yigal M. Pinto, Roddy Walsh, Ahmad S. Amin, Arthur A. M. Wilde, Stuart A. Cook, Sanjay K. Prasad, Paul J. R. Barton, Declan P. O’Regan, R. T. Lumbers, Anuj Goel, Rafik Tadros, Michelle Michels, Hugh Watkins, Connie R. Bezzina, James S. Ware","doi":"10.1038/s41588-025-02094-5","DOIUrl":"https://doi.org/10.1038/s41588-025-02094-5","url":null,"abstract":"<p>Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435024","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":"ImmuneLENS characterizes systemic immune dysregulation in aging and cancer","authors":"Robert Bentham, Thomas P. Jones, James R. M. Black, Carlos Martinez-Ruiz, Michelle Dietzen, Maria Litovchenko, Kerstin Thol, Thomas B. K. Watkins, Chris Bailey, Oriol Pich, Zhihui Zhang, Peter Van Loo, Charles Swanton, Nicholas McGranahan","doi":"10.1038/s41588-025-02086-5","DOIUrl":"https://doi.org/10.1038/s41588-025-02086-5","url":null,"abstract":"<p>Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435022","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":"Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy","authors":"Rafik Tadros, Sean L. Zheng, Christopher Grace, Paloma Jordà, Catherine Francis, Dominique M. West, Sean J. Jurgens, Kate L. Thomson, Andrew R. Harper, Elizabeth Ormondroyd, Xiao Xu, Pantazis I. Theotokis, Rachel J. Buchan, Kathryn A. McGurk, Francesco Mazzarotto, Beatrice Boschi, Elisabetta Pelo, Michael Lee, Michela Noseda, Amanda Varnava, Alexa M. C. Vermeer, Roddy Walsh, Ahmad S. Amin, Marjon A. van Slegtenhorst, Nicole M. Roslin, Lisa J. Strug, Erika Salvi, Chiara Lanzani, Antonio de Marvao, Jason D. Roberts, Maxime Tremblay-Gravel, Genevieve Giraldeau, Julia Cadrin-Tourigny, Philippe L. L’Allier, Patrick Garceau, Mario Talajic, Sarah A. Gagliano Taliun, Yigal M. Pinto, Harry Rakowski, Antonis Pantazis, Wenjia Bai, John Baksi, Brian P. Halliday, Sanjay K. Prasad, Paul J. R. Barton, Declan P. O’Regan, Stuart A. Cook, Rudolf A. de Boer, Imke Christiaans, Michelle Michels, Christopher M. Kramer, Carolyn Y. Ho, Stefan Neubauer, Paul M. Matthews, Arthur A. M. Wilde, Jean-Claude Tardif, Iacopo Olivotto, Arnon Adler, Anuj Goel, James S. Ware, Connie R. Bezzina, Hugh Watkins","doi":"10.1038/s41588-025-02087-4","DOIUrl":"https://doi.org/10.1038/s41588-025-02087-4","url":null,"abstract":"<p>Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, <i>SVIL</i>, which encodes the actin-binding protein supervillin, showing that rare truncating <i>SVIL</i> variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"1 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435023","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}