Nature genetics最新文献

{"title":"Imputation of fluid intelligence scores reduces ascertainment bias and increases power for analyses of common and rare variants","authors":"David M. van den Berg, Daniel S. Malawsky, Wei Huang, Petr Danecek, Klaudia Walter, Georgios Kalantzis, Isaac Wade, Duncan Palmer, Ewan Birney, Karin J. H. Verweij, Dirk J. A. Smit, Sarah J. Lindsay, Matthew E. Hurles, Abdel Abdellaoui, Hilary C. Martin","doi":"10.1038/s41588-026-02787-5","DOIUrl":"https://doi.org/10.1038/s41588-026-02787-5","url":null,"abstract":"Studying the genetics of intelligence provides insight into the neurobiology of cognitive function and rare neurodevelopmental conditions. Here we integrated fluid intelligence (FI) tests across different UK Biobank measures and imputed FI for unmeasured individuals, increasing the sample size from ~270,000 to >455,000. We show through extensive validation that the imputed phenotype genetically resembles measured FI, although some noncognitive signal likely remains. Combining measured and imputed FI increases the number of independent significant common SNP associations from 390 to 550 and reduces the ascertainment bias introduced by FI test participants being, on average, more educated. Rare variant analyses identify 26 significantly associated genes (false discovery rate < 1%), including 8 without strong prior evidence of involvement in intelligence or neurodevelopmental conditions, which replicate in aggregate in external cohorts. Our results demonstrate that imputed intelligence can boost power for genetic discovery and support its use to help discover new neurodevelopmental condition-associated genes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"53 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087887","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 heritability-optimized method for functional prioritization of rare coding variants in complex traits","authors":"Keona Pang,&nbsp;Nazia Pathan,&nbsp;Ann Le,&nbsp;Alice Man,&nbsp;Josef Graf,&nbsp;Yanran Li,&nbsp;Guilherme L. da Rocha,&nbsp;Elad Shemesh,&nbsp;Daria Grafodatskaya,&nbsp;Michael R. Chong,&nbsp;Guillaume Paré","doi":"10.1038/s41588-026-02766-w","DOIUrl":"10.1038/s41588-026-02766-w","url":null,"abstract":"Population sequencing studies are uncovering millions of missense rare variants (RVs) implicated in the ‘missing heritability’ of complex diseases, yet distinguishing functional from neutral variation remains challenging. Here we present rare variant heritability-optimized scores (RovHer), a heritability-optimized method for inferring a variant’s probability of being functional (that is, its contribution to trait variance). RovHer leverages exome-wide association statistics across 4,927,334 RVs and uses multivariate adaptive regression splines to integrate 75 variant- and gene-level features without a priori constraints. Across 21 traits in up to 357,086 UK Biobank European individuals, the top 1% of RovHer-prioritized missense RVs (m = 13,410) explained, on average, 16.1% of total RV heritability, a 10-fold gain over 7 alternative methods (average 1.5%; range 1.2–2.3%). RovHer’s predictions are independent of allele frequency, generalize in a multi-ancestry replication and effectively identify high-risk carriers of severe clinical outcomes across 17 monogenic gene–trait pairs. Our tool showcases the value of missense RVs in population risk stratification. This study presents RovHer, a heritability-optimized scoring method for estimating the functional impact of rare variants, which is applied to the UK Biobank to demonstrate its ability to enrich for missense rare variants that maximally explain complex trait heritability.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2502-2513"},"PeriodicalIF":25.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087594","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":"Single-allele nanoscale mapping of regulatory variants","authors":"Joseph C. Hamley,&nbsp;Weijiao Zhang,&nbsp;Daniel Willmott,&nbsp;Lucia Y. Chen,&nbsp;Vassilena Sharlandjieva,&nbsp;Hangpeng Li,&nbsp;James L. T. Dalgleish,&nbsp;Nicholas Denny,&nbsp;Gaurav Agarwal,&nbsp;Lance Hentges,&nbsp;Bora Ozcan,&nbsp;Roman M. Doll,&nbsp;Ye Wei,&nbsp;Simone G. Riva,&nbsp;Samvida S. Venkatesh,&nbsp;Marta Arachi,&nbsp;Devika Agarwal,&nbsp;Evgeny E. Akkuratov,&nbsp;Matthew Baxter,&nbsp;Tatjana Sauka-Spengler,&nbsp;Calliope A. Dendrou,&nbsp;Thomas A. Milne,&nbsp;Jim R. Hughes,&nbsp;James O. J. Davies","doi":"10.1038/s41588-026-02776-8","DOIUrl":"10.1038/s41588-026-02776-8","url":null,"abstract":"Millions of genetic variants are linked to human disease but identifying underlying mechanisms is challenging because most variants are noncausal and lie within the noncoding genome. We developed a Micro Capture-C variant-to-function platform (MCCv) based on analysis of single-allele chromatin structure. This can identify changes in nanoscale chromatin architecture and link variants in cis-regulatory elements to target genes. Furthermore, MCCv can phase other heterozygous variants within a locus to link regulatory variants to allelically imbalanced gene expression and directly read out variant effects on chromatin interactions after genome editing. With this approach, we investigated 405 cis-regulatory elements linked to immune-mediated inflammatory disease in CD4+ T cells. We uncovered a previously undescribed gain-of-function mechanism, which increases risk of autoimmunity through creation of a neo-CTCF motif that blocks super-enhancer contacts with the SESN3 promoter. We showed that SESN3 regulates mammalian target of rapamycin by sensing tryptophan and demonstrated its role in autoimmunity using mouse models. This study uses high-resolution, allele-specific chromatin architecture to identify causal gene-regulatory mechanisms in inflammatory diseases and uncovers a mechanism by which a neo-CTCF site promotes autoimmunity.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2660-2672"},"PeriodicalIF":25.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02776-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087636","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":"Loss of lineage fidelity underpins drug resistance in Kras-mutant lung cancer","authors":"","doi":"10.1038/s41588-026-02767-9","DOIUrl":"10.1038/s41588-026-02767-9","url":null,"abstract":"Durable clinical responses to KRAS inhibition are limited by acquired resistance. Using genetically engineered mouse models of Kras-mutant lung cancer, we demonstrate that lineage fidelity modulates drug-tolerant residual disease and distinct trajectories of therapeutic resistance, as well as dependence on oncogenic KRAS.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2433-2434"},"PeriodicalIF":25.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112341","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":"Reactivation of the embryonic ζ-globin gene ameliorates severe forms of α-thalassemia","authors":"Siyu Liu \u0000 (,&nbsp;),&nbsp;Ayesha Ejaz,&nbsp;Andrew J. King,&nbsp;Aude-Anais Olijnik,&nbsp;Jacqueline Sloane-Stanley,&nbsp;Caroline Scott,&nbsp;Ali Amid,&nbsp;Daniel Biggs,&nbsp;Benjamin Davies,&nbsp;Jennifer Eglinton,&nbsp;Gabriella Martyn,&nbsp;Merlin Crossley,&nbsp;Christian Babbs,&nbsp;Mira T. Kassouf,&nbsp;Douglas R. Higgs","doi":"10.1038/s41588-026-02770-0","DOIUrl":"10.1038/s41588-026-02770-0","url":null,"abstract":"Hemoglobinopathies are the most common inherited anemias worldwide. While most carriers are asymptomatic or mildly affected, severe forms of α-thalassemia, including severe hemoglobin H (HbH) disease and surviving individuals with Hb Bart’s hydrops fetalis syndrome (BHFS), require lifelong transfusion support or stem cell transplantation. Reactivating the silenced embryonic α-like globin (ζ-globin) gene is a promising approach for treating these diseases. Here we identify the key cis-regulatory elements responsible for silencing the ζ-globin gene in definitive erythroid cells and subsequently develop gene-editing strategies that reactivate ζ-globin expression to therapeutically relevant levels. In a preclinical mouse model of BHFS, we show that this strategy rescues the otherwise prenatal lethal condition until late in development (E17.5). Using primary erythroid cells derived from patients with HbH disease and BHFS, we show that these approaches reactivate ζ-globin expression to levels exceeding those achieved in the mouse model, producing therapeutic levels of α-like globin. Liu et al. identify cis-regulatory elements that silence the embryonic ζ-globin gene in definitive erythroid cells. Gene-editing strategies reactivate ζ-globin expression to therapeutically relevant levels in mouse and human disease models.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2619-2629"},"PeriodicalIF":25.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02770-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087840","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":"Single-cell profiling and genetic regulation of alternative polyadenylation in the human brain","authors":"Jiuhong Nan, Carles A. Boix, Shaohui Shi, Xiaoxi Fan, Jiacheng Ni, Kai Wang, Xiaoyu Shuai, Ke Ding, Puqi Wu, Yao An, Na Sun, Lei Hou, Kexuan Chen, Xianpei Huang, Chengyu Li, Leyla Akay, Kate Louderback, Hiba Nawaid, Yongjin P. Park, Xudong Fu, Chong Liu, Xiaoyu Li, Yafei Yin, Wei Mo, Zhanghua Yang, Weirui Ma, Xinyang Hu, David A. Bennett, Manolis Kellis, Li-Huei Tsai, Shamil Sunyaev, Jingyun Li, Xushen Xiong","doi":"10.1038/s41588-026-02758-w","DOIUrl":"https://doi.org/10.1038/s41588-026-02758-w","url":null,"abstract":"Alternative polyadenylation (APA) has a central role in regulation of the fate of mRNA and exhibits high variability in the brain and in neurons. However, brain APA regulation has not been mapped at cell type resolution, and the genetic control of APA in brain cell types and its contribution to genetic disease have remained unclear. Here we report a single-cell atlas of APA of the aged human brain across 2 million cells from 379 human postmortem brains across individuals with and without Alzheimer’s disease (AD). We show that APA provides an independent mechanistic layer for understanding gene regulatory changes in AD, as genes with APA alterations are distinct from those with expression changes but often converge to similar pathways, including microglial activation and microtubule transport in neurons. We integrate APA variation with whole-genome sequencing to identify cell-type-resolved 3′ untranslated region quantitative trait loci (3′aQTLs) for 4,288 genes. We find that 3′aQTLs preferentially colocalize with pQTLs over eQTLs. Across 17 brain traits and diseases, we identify 168 GWAS loci dependent on 3′aQTLs, of which only 17.5% are shared with eQTLs. These include PLEKHA1 and APOC2 for AD, PAK6 and AP3B2 for schizophrenia, NDUFA13 for bipolar disorder, MTCH2 for multiple brain traits, and SNCA, the top locus in Parkinson’s disease. We show that 3′ untranslated region choice alters SNCA mRNA localization within the cell, consistent with the observation that the SNCA risk locus acts in an eQTL-independent manner in neurons and oligodendrocytes. Our results provide a cell-type-specific foundation to interrogate the cis and trans regulation of APA and to understand the contribution to disease heritability of this key post-transcriptional layer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"13 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087598","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":"ArchMap is a web-based platform for reference-based analysis of single-cell datasets","authors":"Mohammad Lotfollahi,&nbsp;Chelsea Bright,&nbsp;Ronald Skorobogat,&nbsp;Mohammad Moghareh Dehkordi,&nbsp;Xavier George,&nbsp;Simon Richter,&nbsp;Vladimir A. Shitov,&nbsp;Aleksandra Topalova,&nbsp;Helena Melcher,&nbsp;Noah Nussbaumer,&nbsp;Annika Fomm,&nbsp;Malte D. Luecken,&nbsp;Fabian J. Theis","doi":"10.1038/s41588-026-02756-y","DOIUrl":"10.1038/s41588-026-02756-y","url":null,"abstract":"Leveraging single-cell reference atlases to analyze new data has brought about a paradigm shift in single-cell data science akin to the first reference genome in genomics. However, methods for performing this mapping require computational expertise and, oftentimes, considerable compute power, limiting access for researchers who may benefit the most. Here ArchMap, a no-code query-to-reference mapping tool, removes this barrier by providing all-in-one automated mapping, cell-type annotation and collaborative features to analyze single-cell datasets from a wide range of integrated, often published, reference atlases and allows the extension of atlases with the growing Human Cell Atlas and related efforts. This paves the way for a democratization of reference mapping capabilities. Existing software for mapping single-cell datasets onto reference atlases often requires coding expertise or a license. ArchMap is a free no-code query-to-reference mapping web tool compatible with Python-based mapping methods.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2469-2473"},"PeriodicalIF":25.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02756-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087597","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":"Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance","authors":"Nicolas Mathey-Andrews,&nbsp;Carrie L. Rodriguez,&nbsp;Bing Shui,&nbsp;Agata L. Patriotis,&nbsp;William M. Rideout III,&nbsp;Victor Z. Chen,&nbsp;Ileana Murazzi,&nbsp;Phaedra Ghazi,&nbsp;Milton R. Cornwall-Brady,&nbsp;Manyuan Liu,&nbsp;Morgan G. Heileman,&nbsp;Marianna Trakala,&nbsp;Carla P. Concepcion-Crisol,&nbsp;Dian Yang,&nbsp;Tyler Jacks","doi":"10.1038/s41588-026-02768-8","DOIUrl":"10.1038/s41588-026-02768-8","url":null,"abstract":"Primary and acquired resistance to targeted therapy represent significant challenges to durable treatment responses in oncology. In lung adenocarcinoma, KRAS inhibitors are hampered by incomplete clinical responses and acquired resistance. Here we treated genetically engineered mouse models of Kras-driven lung adenocarcinoma with KRAS inhibitors to model these conditions. Initial treatment response was rapid but incomplete, with residual tumor burden transcriptionally resembling alveolar epithelial cells. With continued treatment, we invariably observed genetic Kras amplification as a resistance mechanism. To model oncogene-independent resistance, we used functional CRISPR approaches to promote squamous lineage transformation. We found that ∆Np63 was sufficient to transform alveolar organoids to a squamous state in vitro, conferring insensitivity to KRAS inhibition. In vivo, Nkx2-1 loss and/or ectopic Sox2 expression poised tumors for squamous lineage commitment. Squamous-transformed tumors did not exhibit evidence of KRAS/MAPK reactivation, underscoring the role for lineage transcription factors and histologic transformation in mediating KRAS independence. KRAS-mutant lung cancers frequently develop resistance to targeted inhibition. This study demonstrates that lineage plasticity shapes oncogene dependence during response and resistance to KRAS inhibition, establishing new models of histologic transformation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2605-2618"},"PeriodicalIF":25.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087596","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":"Defining pathogenic macrophages in the fibrotic niche of human chronic liver disease","authors":"","doi":"10.1038/s41588-026-02778-6","DOIUrl":"10.1038/s41588-026-02778-6","url":null,"abstract":"Monocyte-derived macrophages are central in liver fibrosis pathogenesis, but the specific phenotype of the pro-fibrotic subpopulation is unknown. Using a liver single-cell atlas from 77 patients with chronic liver disease, we resolve 2 subpopulations of TREM2+ scar-associated macrophages and identify OLR1 as a candidate therapeutic target to selectively modulate pro-fibrotic macrophage functions and thereby attenuate liver fibrosis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2427-2428"},"PeriodicalIF":25.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081503","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":"Genetics and treatment history influence clonal hematopoiesis risk after PARP inhibitor therapy","authors":"","doi":"10.1038/s41588-026-02749-x","DOIUrl":"10.1038/s41588-026-02749-x","url":null,"abstract":"PARP inhibitors and platinum chemotherapy both promote expansion of blood stem cell clones carrying leukemia-associated mutations, but inherited defects in homologous recombination limit this process. These findings reveal that therapy-related leukemia risk may depend on an interaction between treatment history and inherited genetics.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2431-2432"},"PeriodicalIF":25.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081507","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}