Nature genetics最新文献

{"title":"Rare variant effect estimation and polygenic risk prediction","authors":"Kisung Nam, Minjung Kho, Wei Zhou, Bhramar Mukherjee, Seunggeun Lee","doi":"10.1038/s41588-026-02705-9","DOIUrl":"10.1038/s41588-026-02705-9","url":null,"abstract":"Due to their low frequency, estimating the effects of rare variants is challenging. Here we propose RareEffect, a method that first estimates gene-based or region-based heritability and then each variant effect size using an empirical Bayes approach. Our method uses a variance component model, which is popular in rare variant tests, and is designed to provide two levels of effect sizes—gene/region level and variant level—that can provide better interpretation. To adjust for the case–control imbalance in phenotypes, our approach uses a fast implementation of the Firth bias correction. We demonstrate the accuracy and computational efficiency of our method through extensive simulations and analysis of UK Biobank whole-exome sequencing data for 100 traits. Additionally, we show that the effect sizes obtained from our model can be leveraged to improve polygenic score performance, thereby outperforming recently developed methods for rare variant polygenic scoring. RareEffect is an accurate and computationally efficient Bayesian method for estimating rare variant effect sizes. These estimates can be leveraged to improve polygenic prediction models, thereby outperforming other methods for rare variant polygenic scoring.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2381-2388"},"PeriodicalIF":25.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02705-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769285","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":"Bridging the gap between GWAS and network medicine with GNExT","authors":"Lis Arend, Fabian Woller, Bastienne Rehor, David Emmert, Johannes Frasnelli, Christian Fuchsberger, David B. Blumenthal, Markus List","doi":"10.1038/s41588-026-02708-6","DOIUrl":"10.1038/s41588-026-02708-6","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2413-2415"},"PeriodicalIF":25.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795709","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":"SpatialVista as a unified ecosystem for high-performance visualization and exploration of 3D spatial transcriptomics data","authors":"Wenjie Wei, Lounan Li, Liyang Song, Wenhao Chen, Kai Wang, Minmin Guo, Jian Yang","doi":"10.1038/s41588-026-02696-7","DOIUrl":"10.1038/s41588-026-02696-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2063-2065"},"PeriodicalIF":25.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761209","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":"Spatial analysis of head and neck cancer identifies two ecosystems with distinct modes of epithelial-to-mesenchymal transition","authors":"Dor Simkin, Thomas F. Barrett, Lingling Zhang, Michael J. Moore, Alissa C. Greenwald, Noam Galili, Michael Mints, Salma Ramadan, Victoria Yu, Riley D. Z. Mullins, Jesse Zaretsky, Porter Bischoff, Douglas Adkins, Wade L. Thorstad, Sana D. Karam, Randall C. Paniello, Jason T. Rich, Ryan S. Jackson, Patrik Pipkorn, Paul A. Zolkind, Guangyong Peng, R. Alex Harbison, Rebecca Chernock, Anuraag S. Parikh, Sidharth V. Puram, Itay Tirosh","doi":"10.1038/s41588-026-02723-7","DOIUrl":"10.1038/s41588-026-02723-7","url":null,"abstract":"Head and neck squamous cell carcinoma (HNSCC) shows substantial intra- and inter-tumoral heterogeneity. We mapped tumor architecture across HPV-positive and HPV-negative HNSCC through spatial transcriptomics (n = 26). HPV-positive tumors display hypercellularity, higher lymphocyte presence, enriched hypoxia and reduced partial epithelial-to-mesenchymal transition (p-EMT) in malignant cells. We observed two distinct spatial architectures of p-EMT: p-EMT edge, where p-EMT is coupled to fibroblasts at the invasive front via TGFβ, and p-EMT core, in which tumor-infiltrating immunosuppressive macrophages and neutrophils induce p-EMT via oncostatin M in the core of tumor nests. These two p-EMT patterns were consistent across multiple samples from the same tumor, suggesting they are tumor-wide features. Together, these findings reveal that distinct interactions in the tumor microenvironment converge on a similar p-EMT cellular phenotype, but in a different spatial pattern that may have potential biological and clinical implications for our understanding of invasion, immune modulation and new targeted therapeutics for HNSCC. A spatially resolved analysis of HPV-positive and HPV-negative head and neck cancers identifies two distinct spatial localizations of partial epithelial-to-mesenchymal transition, in the tumor core or edge, which associate with specific immune contexts and clinical outcomes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2240-2253"},"PeriodicalIF":25.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728970","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":"PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures","authors":"Audrey Coulon, Florian Rabiller, Mari Takalo, Avishek Roy, Alexandre Pelletier, Henna Martiskainen, Dolores Siedlecki-Wullich, Nina Lannette-Weimann, Naďa Majerníková, Arthur Grenon, Vance Gao, Anaël Erhardt, Anne Pernodet, Morgane Lemaire, Floriane Limoge, Pauline Walle, Tiago Mendes, Karine Guyot, Célia Lemeu, Lukas-Iohan Carvalho, Ana Raquel Melo de Farias, Marc Hulsman, Chloé Najdek, Alejandra Freire-Regatillo, Orthis Saha, Philippe Amouyel, Camille Charbonnier, Jean-François Deleuze, Orio Dols-Icardo, Heli Jeskanen, Roosa-Maria Willman, Teemu Kuulasmaa, Mitja Kurki, John Hardy, Sami Heikkinen, Henne Holstege, Petra Mäkinen, Gaël Nicolas, Simon Mead, Michael Wagner, Alfredo Ramirez, Tuomas Rauramaa, Aarno Palotie, Rebecca Sims, Hilkka Soininen, John van Swieten, Julie Williams, Céline Bellenguez, Carla Gelle, Erwan Lambert, Marcos R. Costa, Julia TCW, Enrico Glaab, Anne-Marie Ayral, Florie Demiautte, Benjamin Grenier-Boley, Manon Muntaner, Delphine Eberlé, Séverine Deforges, Joel T. Haas, Devrim Kilinc, Christophe Mulle, Julien Chapuis, Mikko Hiltunen, Julie Dumont, Jean-Charles Lambert","doi":"10.1038/s41588-026-02709-5","DOIUrl":"10.1038/s41588-026-02709-5","url":null,"abstract":"We developed a high-content screening to investigate how Alzheimer’s disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons. This study demonstrates that downregulation of PLCG2, primarily in neurons, impairs synaptic function and elevates amyloid-β levels and Tau protein phosphorylation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2164-2176"},"PeriodicalIF":25.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02709-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728971","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":"Correlations between causal effect sizes of proximal SNPs vary with functional annotations and implicate stabilizing selection","authors":"Martin Jinye Zhang, Arun Durvasula, Colby Chiang, Evan M. Koch, Benjamin J. Strober, Huwenbo Shi, Alison R. Barton, Samuel S. Kim, Omer Weissbrod, Po-Ru Loh, Steven Gazal, Shamil Sunyaev, Alkes L. Price","doi":"10.1038/s41588-026-02712-w","DOIUrl":"10.1038/s41588-026-02712-w","url":null,"abstract":"Causal disease effect sizes of proximal single-nucleotide polymorphisms (SNPs) are widely assumed to be independent but could be correlated. Here we introduce a new method, linkage disequilibrium SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs; LDSPEC produced robust estimates in simulations. Analyzing 70 UK Biobank diseases and traits (average N = 305,646), we detected significantly non-zero SNP-pair effect correlations (for example, −0.37 ± 0.09 for low-frequency positive linkage disequilibrium 0–100-bp SNP pairs) that decayed with distance and varied with allele frequency and linkage disequilibrium between SNPs. SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances. Consequently, SNP heritability estimates were smaller than estimates of the sum of causal effect size variances across SNPs, particularly for certain functional annotations. We recapitulated our findings via forward simulations involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection. This study generates a method to detect correlation of causal complex trait effect sizes between proximal SNPs, finding variation by functional annotation and support for stabilizing selection, whereby proximal SNPs in positive linkage disequilibrium have effects in opposite directions.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2361-2370"},"PeriodicalIF":25.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728972","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":"hnRNPK condensates facilitate enhancer–promoter looping and RNA polymerase II recruitment","authors":"Rong Ye, Hailian Zhao, Juan Chen, Qigui Wu, Di Wang, Zhaokui Cai, Ruoyan Wang, Jingxin Li, Tiantian Cheng, Ming Zhang, Wanglong Liu, Ruiyun Yang, Jie Zhou, Zhen Yuan, Bowen Liu, Changchang Cao, Shuoji Zhu, Xing Li, Jinsong Li, Tengfei Zhang, Ping Zhu, Yuanchao Xue","doi":"10.1038/s41588-026-02710-y","DOIUrl":"10.1038/s41588-026-02710-y","url":null,"abstract":"Enhancer RNAs interact with promoter-derived RNAs to dictate enhancer–promoter looping, but the RNA-binding protein that mediates this process has remained unidentified. Here we identify hnRNPK as a general structural regulator that preferentially binds to nascent RNAs transcribed from enhancer and promoter regions, promoting enhancer–promoter looping and transcriptional activation. We further show that hnRNPK forms phase-separated, cavity-containing condensates that encapsulate RNA polymerase II (Pol II) via its RPB3 subunit, facilitating chromatin looping and potentially enabling recruitment of Pol II from enhancers to promoters through protein dimerization. Notably, a mutation associated with Au–Kline syndrome in hnRNPK (c.953+1dupG) alters its condensates from a liquid-like to a gel-like state, leading to developmental defects in knock-in mice. Fibroblasts derived from these mutants display reduced enhancer–promoter looping and decreased Pol II recruitment at promoters of key developmental genes. These findings suggest that hnRNPK is a structural regulator of enhancer–promoter communication and highlight the importance of RNA–RNA interactions mediated by RNA-binding proteins in transcriptional regulation. This study shows that hnRNPK binds nascent RNAs transcribed from enhancers and promoters to promote enhancer–promoter looping and transcriptional activation, potentially via recruitment of Pol II through phase separation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2320-2334"},"PeriodicalIF":25.5,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723646","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":"Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease","authors":"Donghoon Lee, James M. Vicari, Christian Porras, Collin Spencer, Milos Pjanic, Xinyi Wang, Seon Kinrot, Philipp Weiler, Roman Kosoy, Jaroslav Bendl, Prashant N M, Konstantina Psychogyiou, Periklis Malakates, Evelyn Hennigan, Jennifer Monteiro Fortes, Shiwei Zheng, Karen Therrien, Deepika Mathur, Steven P. Kleopoulos, Zhiping Shao, Stathis Argyriou, Marcela Alvia, Clara Casey, Aram Hong, Kristin G. Beaumont, Robert Sebra, Christopher P. Kellner, David A. Bennett, Guo-Cheng Yuan, Georgios Voloudakis, Fabian J. Theis, Vahram Haroutunian, Gabriel E. Hoffman, John F. Fullard, Panos Roussos","doi":"10.1038/s41588-026-02716-6","DOIUrl":"10.1038/s41588-026-02716-6","url":null,"abstract":"Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer’s disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell–cell interaction analyses prioritize APOE–SORL1 and APOE–TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery. Molecular profiling of myeloid cells from the prefrontal cortex of 1,607 donors with varying degrees of Alzheimer’s disease neuropathology delineates distinct myeloid subtypes and identifies changes associated with aging and disease progression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2152-2163"},"PeriodicalIF":25.5,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713300","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":"Prevalence and chronology of colibactin-associated mutational processes and their microbiome spectra in Japanese colorectal cancer","authors":"Satoshi Shiba, Shinichi Yachida, Sayaka Mizutani, Yasushi Totoki, Hiromi Nakamura, Natsuko Hama, Norikatsu Miyoshi, Yasuhito Arai, Mihoko Saito-Adachi, Hirokazu Kimura, Yoshito Hayashi, Hiroyuki Takamaru, Koji Tanaka, Rie Hayashi, Hirofumi Rokutan, Shoko Ikuta, Yukihide Kanemitsu, Yuichiro Doki, Hidetoshi Eguchi, Satoshi Hattori, Yutaka Saito, Takuji Yamada, Tatsuhiro Shibata","doi":"10.1038/s41588-026-02692-x","DOIUrl":"10.1038/s41588-026-02692-x","url":null,"abstract":"The incidence of colorectal cancer (CRC) has risen in recent decades, with a disproportionate increase observed among younger individuals in Japan and other countries. The etiological contribution of the gut microbiota to CRC pathogenesis is recognized, yet the mechanisms involved remain to be fully clarified. Here we integrated whole-genome sequencing (WGS) and transcriptome profiling of CRC with whole-genome metagenomic sequencing of fecal samples to interrogate host–microbiome interactions at high resolution. Application of interpretable artificial intelligence enabled the stratification of CRC into four distinct microbiome-informed subtypes. WGS analysis identified mutational signatures SBS88 and ID18, linked to colibactin exposure, as early clonal events detected in 44.8% of non-hypermutated patients. Notably, these signatures were significantly more frequent among patients born after the 1960s. Microbiome-based subclassification revealed subtype-specific clinical and molecular features. Collectively, our findings indicate that colibactin exposure constitutes a prevalent and potentially modifiable risk factor for CRC in the Japanese population. Integrative analyses of whole-genome and transcriptome sequencing on Japanese colorectal cancer along with whole-genome metagenomic sequencing on fecal samples characterize host–microbiome interactions and colibactin-associated mutational signatures.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2211-2225"},"PeriodicalIF":25.5,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02692-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148707140","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":"Cellular atlas of endocrine signaling","authors":"Kyle Vogan","doi":"10.1038/s41588-026-02719-3","DOIUrl":"10.1038/s41588-026-02719-3","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 8","pages":"1749-1749"},"PeriodicalIF":25.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689567","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}