Nature genetics最新文献

{"title":"Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis","authors":"Paul J. Hop, Maarten Kooyman, Brendan J. Kenna, Ramona A. J. Zwamborn, Kristel R. van Eijk, Yan Wang, Charlotte H. van Dijk, Erwin Bekema, Wouter van Rheenen, Paul Beele, Joke J. F. A. van Vugt, Project MinE ALS sequencing Consortium, NYGC ALS Consortium, FALS sequencing Consortium, GTAC Consortium, Ahmad Al Khleifat, Alfredo Iacoangeli, Johnathan Cooper-Knock, Bradley N. Smith, Simon Topp, Anneke J. van der Kooi, Vera Fominykh, Vivian Drory, Yossef Lerner, Yehuda Shovman, Dominic B. Rowe, Kelly L. Williams, Russell L. McLaughlin, Jessica Hurt, Yunfeng Huang, Chia-Yen Chen, Ellen Tsai, Heiko Runz, Eleonora Aronica, Ewout J. N. Groen, Michael A. van Es, R. Jeroen Pasterkamp, Sali M. K. Farhan, Fleur C. Garton, Allan F. McRae, Pamela A. McCombe, Robert D. Henderson, Dongsheng Fan, Lenka Šlachtová, Helle Høyer, Agnes L. Nishimura, Ruben J. Cauchi, Lev Brylev, Boris Rogelj, Blaž Koritnik, Janez Zidar, Teresa Salas, Jesus S. Mora Pardina, Marc Gotkine, Monica Povedano, Philippe Corcia, Patrick Vourc’h, Philippe Couratier, Markus Weber, Matthew C. Kiernan, Roger Pamphlett, Ian P. Blair, Mamede de Carvalho, Nazli A. Başak, Caroline Ingre, Peter M. Andersen, Lorne Zinman, Ekaterina Rogaeva, Ian R. MacKenzie, Nicolas Dupre, Guy A. Rouleau, Bryan J. Traynor, Nicola Ticozzi, Adriano Chiò, Vincenzo Silani, Orla Hardiman, Hemali Phatnani, Matthew B. Harms, Clifton L. Dalgard, Jonathan D. Glass, John E. Landers, Philip Van Damme, Karen E. Morrison, Pamela J. Shaw, Chris E. Shaw, Ammar Al-Chalabi, Leonard H. van den Berg, Kevin P. Kenna, Jan H. Veldink","doi":"10.1038/s41588-026-02535-9","DOIUrl":"10.1038/s41588-026-02535-9","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies. Single-variant and ultrarare variant burden analyses leveraging exome sequencing data from 22 cohorts identify new risk genes for amyotrophic lateral sclerosis and show cumulative effects of several rare variants on disease risk.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"717-725"},"PeriodicalIF":29.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02535-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147584054","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":"The inactive X chromosome as a female protector in autism and beyond","authors":"Maya Talukdar, David C. Page","doi":"10.1038/s41588-026-02534-w","DOIUrl":"10.1038/s41588-026-02534-w","url":null,"abstract":"Female individuals require greater autosomal genetic risk than male individuals to manifest autism, yet the biological basis of this ‘female protective effect’ (FPE) remains unknown. Based on insights into the human sex chromosomes, we propose that the FPE arises from higher expression of a subset of X-linked genes in females due to transcription from both the active (Xa) and inactive (Xi) X chromosomes. These higher expression levels enable females to buffer mutations in autosomal genes and in pathways regulated by Xi-expressed genes. This framework unifies epidemiological, genetic and mechanistic observations across autism and other male-biased congenital and developmental disorders, suggesting that the combined activity of Xa and Xi allows females to better tolerate autosomal genetic risk across many pediatric conditions. If correct, this reshapes our understanding of sex differences in human disease and positions Xi as a genetic suppressor of autosomal mutations in autism and beyond. In this Perspective, Talukdar and Page propose that gene expression from both the active and inactive X chromosomes in female individuals can explain the ‘female protective effect’ observed in autism and other male-biased pediatric disorders.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"687-694"},"PeriodicalIF":29.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581708","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":"Genome-wide fine-mapping improves identification of causal variants","authors":"Yang Wu, Zhili Zheng, Loic Thibaut, Tian Lin, Qian Feng, Hao Cheng, Loic Yengo, Michael E. Goddard, Naomi R. Wray, Peter M. Visscher, Jian Zeng","doi":"10.1038/s41588-026-02549-3","DOIUrl":"10.1038/s41588-026-02549-3","url":null,"abstract":"Fine-mapping refines genotype–phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic loci and do not account for the global genetic architecture. Here we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) with functional annotations and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods across several metrics, including error control, mapping power, resolution, precision, replication rate and trans-ancestry phenotype prediction. Across 48 complex traits, we identify credible sets that collectively explain 18% of the SNP-based heritability $$({h}_{mathrm{SNP}}^{2})$$ on average, with 30% credible sets located outside genome-wide significant loci. Leveraging the genetic architecture estimated from GWFM, we predict that fine-mapping over 50% of $${h}_{mathrm{SNP}}^{2}$$ would require an average of 2 million samples. Finally, as proof-of-principle, we highlight a known causal variant at FTO influencing body mass index and identify new missense causal variants influencing schizophrenia and Crohn’s disease risk. A new method for performing genome-wide fine-mapping with functional annotations outperforms current methods across several metrics, including error control, mapping power, resolution, precision, replication rate and cross-ancestry phenotype prediction.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"940-951"},"PeriodicalIF":29.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02549-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581621","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":"Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder","authors":"Daniel Greene, Rodrigo Mendez, Jon Lees, Mafalda Barbosa, Alessandro Bruselles, Luigi Chiriatti, Federico Ferraro, Cecilia Mancini, Rachel Schot, Frank Sleutels, Enrico Bertini, Devon E. Bonner, Arjan Bouman, Alice S. Brooks, Thomas A. Cassini, Kimberly M. Ezell, Natalia Gomez-Ospina, Tjitske Kleefstra, Michael O’Donoghue, Lynette Rives, Vandana Shashi, Rebecca C. Spillmann, Mohamed Wafik, Undiagnosed Diseases Network, Kathleen Freson, Tahsin Stefan Barakat, Marco Tartaglia, Jonathan A. Bernstein, Andrew D. Mumford, Matthew T. Wheeler, Ernest Turro","doi":"10.1038/s41588-026-02539-5","DOIUrl":"10.1038/s41588-026-02539-5","url":null,"abstract":"We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of RNU2-2 syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity >0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in trans at these variants. A relaxed threshold of >0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive RNU2-2 syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant RNU4-2-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a >90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism. An analysis of rare disease cohorts from the UK, the USA, Italy and the Netherlands identifies a neurodevelopmental disorder caused by biallelic variants in RNU2-2. Individuals with this disorder have substantially reduced levels of U2-2 small nuclear RNA in blood.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"774-781"},"PeriodicalIF":29.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02539-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581631","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":"Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies","authors":"Elsa Leitão, Amandine Santini, Benjamin Cogne, Miriam Essid, Maria Athanasiadou, Christy W. LaFlamme, Pierre Marijon, Virginie Bernard, Kevin Jousselin, Nicolas Chatron, Giulia Barcia, Boris Keren, Cyril Mignot, Perrine Charles, Thomas Besnard, Robin Paluch, Jean-Madeleine de Sainte Agathe, Edith P. Almanza Fuerte, Soham Sengupta, Mathieu Milh, Francis Ramond, Talia Allan, Isabelle An, Camila Araujo, Stéphanie Arpin, Christina Austin-Tse, Stéphane Auvin, Sarah Baer, Nadia Bahi-Buisson, Mads Bak, Magalie Barth, Stéphanie Baulac, Nathalie Bednarek-Weirauch, Matthias Begemann, Mark F. Bennett, Uriel Bensabath, Stéphane Bézieau, Rakia Bhouri, Margaux Biehler, Trine Bjørg Hammer, Julie Bogoin, Emilie Bonanno, Simon Boussion, Céline Bris, Adelaide Brosseau-Beauvir, Ange-Line Bruel, Audrey Briand-Suleau, Julien Buratti, Tristan Celse, Pascal Chambon, Nicole Chemaly, Bertrand Chesneau, Estelle Colin, Maxime Colmard, Cindy Colson, Solène Conrad, Thomas Courtin, Isabelle Creveaux, Anne-Charlotte Cullier, Louis T. Dang, Anne de Saint Martin, Caroline de Vanssay de Blavous Legendre, Bénédicte Demeer, Anne-Sophie Denommé-Pichon, Philine Diekhoff, Stephanie DiTroia, Martine Doco-Fenzy, Christèle Dubourg, Charlotte Dubucs, Stéphanie Ducreux, Louis Dufour, Romain Duquet, Benjamin Durand, Salima El Chehadeh, Miriam Elbracht, Laurence Faivre, Marie Faoucher, Anne Faudet, Sylvie Forlani, Mélanie Fradin, Pauline Gaignard, Benjamin Ganne, Aurore Garde, Justine Géraud, Deepak Gill, Alice Goldenberg, David Grabli, Coraline Grisel, Sophie Gueden, Paul Gueguen, Anne-Marie Guerrot, Agnès Guichet, Tobias B. Haack, Nina Härting, Martin Georg Häusler, Solveig Heide, Theresia Herget, Bénédicte Héron, Delphine Héron, Johanna Herwig, Mathilde Heulin, Tess Holling, Clara Houdayer, Bertrand Isidor, Aurélia Jacquette, Louis Januel, Nolwenn Jean-Marçais, Frank J. Kaiser, Sabine Kaya, Chontelle King, Marina Konyukh, Florian Kraft, Jeremias Krause, Rémi Kirstetter, Alma Kuechler, Ingo Kurth, Kerstin Kutsche, Audrey Labalme, Jean-Serene Laloy, Vincent Laugel, Floriane Le Bricquir, Anne-Sophie Lèbre, Marine Lebrun, Eric Leguern, Jonathan Levy, Nico Lieffering, Stanislas Lyonnet, Kevin Lüthy, Sian M. W. Macdonald, Lamisse Mansour-Hendili, Julien Maraval, Iris Marquardt, Carolin Mattausch, Sandra Mercier, Olfa Messaoud, Godelieve Morel, Jérémie Mortreux, Arnold Munnich, Rima Nabbout, Sophie Nambot, Vincent Navarro, Ashana Neale, Laetitia Nguyen, Mathilde Nizon, Frédérique Nowak, Melanie C. O’Leary, Sylvie Odent, Naomi Meave Ojeda, Valérie Olin, Simone Olivieri, Katrin Õunap, Lynn S. Pais, Eleni Panagiotakaki, Olivier Patat, Laurence Perrin-Sabourin, Florence Petit, Christophe Philippe, Amélie Piton, Marc Planes, Céline Poirsier, Antoine Pouzet, Clément Prouteau, Sylvia Quéméner-Redon, Mathilde Renaud, Anne-Claire Richard, Marlène Rio, Clotilde Rivier, Florence Robin-Renaldo, Paul Rollier, Massimiliano Rossi, Agathe Roubertie, Valentin Ruault, Maïlys Rupin-Mas, Pascale Saugier-Veber, Aline Saunier, Russell Saneto, Elisabeth Sarrazin, Catherine Sarret, Elise Schaefer, Caroline Schluth-Bolard, Amy Schneider, Isabell Schumann, Vladimir B. Seplyarskiy, Stephanie Spranger, Thomas Smol, Marc Sturm, Shamil R. Sunyaev, Brian Sperelakis-Beedham, Sarah L. Stenton, Friedrich Stock, Mylène Tharreau, Deniz Torun, Joseph Toulouse, Harshini Thiyagarajah, Stéphanie Valence, Sophie Valleix, Julien Van-Gils, Laurent Villard, Dorothée Ville, Nathalie Villeneuve, Antonio Vitobello, Aurélie Waernessyckle, Jan Wagner, Yvonne Weber, Dagmar Wieczorek, Tom Witkowski, Manya Yadavilli, Tony Yammine, Khaoula Zaafrane-Khachnaoui, Maha S. Zaki, Alban Ziegler, Nuria C. Bramswig, Alban Lermine, Gael Nicolas, Joseph G. Gleeson, Lynette G. Sadleir, Michael S. Hildebrand, Ingrid E. Scheffer, Nicola Whiffin, Anne O’Donnell-Luria, Heather C. Mefford, Pierre Blanc, Julien Thevenon, Camille Charbonnier, Clément Charenton, Christel Depienne, Gaetan Lesca, Caroline Nava","doi":"10.1038/s41588-026-02547-5","DOIUrl":"10.1038/s41588-026-02547-5","url":null,"abstract":"Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome. Analyses of snRNA genes in a French cohort of people with rare disorders, with validation through international collaboration, identify monoallelic and biallelic variants in RNU2-2 as frequent causes of neurodevelopmental disorders with epilepsy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"782-797"},"PeriodicalIF":29.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02547-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581694","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":"Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy","authors":"Adam Jackson, Alexander J. M. Blakes, Bader Alhaddad, Olivia J. Henry, Angelica M. Delgado-Vega, Elizabeth Wall, Ola Abdelhadi, Shakti Agrawal, Khadijah Bakur, Edward Blair, Angela F. Brady, Helen Brittain, Kate E. Chandler, Natasha Clarke, Miriana Danelli, Nicholas Drinkall, Irene Duba, Frances Elmslie, Jamie Ellingford, Lisa J. Ewans, Andrew P. Fennell, Gabriella Gazdagh, Simon P. Heller, Anna Hammarsjö, Kristina Karrman, Usha Kini, Nicole Lesko, Anna Lindstrand, Rebecca Macintosh, Sahar Mansour, Lara Menzies, Kay Metcalfe, Alison Milhench, Lina Nashef, Raymond T. O’Keefe, Nadja Pekkola Pacheco, Elizabeth E. Palmer, Amitav Parida, Katrina Prescott, Melody Redman, Alessandra Renieri, Chiara Fallerini, Caterina Lo Rizzo, Rani Sachdev, Cas Simons, Sanjay M. Sisodiya, Helen Stewart, Tommy Stödberg, Benito Banos-Pinero, Fulya Taylan, Huw B. Thomas, Flavia Tinella, Samuel Wiafe, Anna Wedell, Nicola Whiffin, Susan Walker, Rocio Rius, Jong Hee Chae, Ann Nordgren, Fowzan Alkuraya, Jenny Lord, Siddharth Banka","doi":"10.1038/s41588-026-02551-9","DOIUrl":"10.1038/s41588-026-02551-9","url":null,"abstract":"Neurodevelopmental disorders (NDDs) affect 2–4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene. Analysis of sequencing data from rare disease cohorts identifies biallelic variants in RNU2-2 underlying a developmental and epileptic encephalopathy associated with reduced U2-2 abundance and clinically distinct from the dominant RNU2-2 disorder.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"798-809"},"PeriodicalIF":29.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02551-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581629","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":"Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity","authors":"Hye In Kim, Christopher DeBoever, Klaudia Walter, Georgios Kalantzis, Chen Li, Sahar V. Mozaffari, Kousik Kundu, Benjamin M. Jacobs, Pedrum Mohammadi-Shemirani, Anthony M. Musolf, Jonathan M. Davitte, Melis A. Aksit, Joseph Gafton, Katrina A. Catalano, Adem Y. Dawed, Robert R. Graham, Bin Guo, Namrata Gupta, Teng Hiang Heng, Karen A. Hunt, Vivek Iyer, Claudia Langenberg, Frederik H. Lassen, Daniel G. MacArthur, Eamonn R. Maher, Cyrielle Maroteau, William G. Newman, Stephen O’Rahilly, Duncan S. Palmer, Iaroslav Popov, Moneeza K. Siddiqui, Michael A. Simpson, Marie Spreckley, John Wright, Genes and Health Research Team, Guillermo del Angel, Slavé Petrovski, Emily R. Holzinger, Joseph C. Maranville, Laura Addis, Richard M. Turner, Karol Estrada, Simone Longerich, Joanna M. M. Howson, Yalda Jamshidi, Eric B. Fauman, Melissa R. Miller, Dorothée Diogo, Richard C. Trembath, Sarah Finer, Hilary C. Martin, David A. van Heel","doi":"10.1038/s41588-026-02553-7","DOIUrl":"10.1038/s41588-026-02553-7","url":null,"abstract":"Genes & Health (G&H) is a biomedical study of adult British Pakistani and Bangladeshi research volunteers enriched for autozygosity. Here we performed whole-exome sequencing in 44,028 G&H participants, establishing a large publicly available South Asian exome resource linked to longitudinal electronic health records. We performed exome-wide association analyses for 645 electronic health record-derived traits under additive and recessive models, and meta-analyses of 33 cardiometabolic traits with UK Biobank, finding more than 100 novel gene–phenotype associations. We identified 2,991 genes with rare biallelic predicted loss-of-function (‘knockout’) genotypes, 546 of which had not been previously reported. We show that drugs targeting genes with knockouts in adults are associated with a 2.2-fold higher likelihood of progressing beyond phase 1 clinical trials. We further illustrate how phenotypic profiles associated with knockout genotypes can enhance efficacy and safety assessment of drug targets and aid in the interpretation of variants with ambiguous clinical significance in autosomal recessive disease genes. An analysis of whole-exome sequencing data linked to longitudinal electronic health records from 44,028 British South Asians finds new gene–phenotype associations and identifies 2,991 genes with rare biallelic predicted loss-of-function genotypes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"821-830"},"PeriodicalIF":29.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02553-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531125","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":"Genomic, phenomic and geographic associations of leukocyte telomere length in the United States","authors":"Tetsushi Nakao, Satoshi Koyama, Buu Truong, Md Mesbah Uddin, Anika Misra, Aniruddh P. Patel, Aarushi Bhatnagar, Victoria Viscosi, Caitlyn Vlasschaert, Alexander G. Bick, Christopher P. Nelson, Veryan Codd, Nilesh J. Samani, Whitney Hornsby, Patrick T. Ellinor, Pradeep Natarajan","doi":"10.1038/s41588-026-02567-1","DOIUrl":"10.1038/s41588-026-02567-1","url":null,"abstract":"Leukocyte telomere length (LTL) is associated with multiple conditions, including cardiovascular diseases and neoplasms, yet their differential associations across diverse individuals are largely unknown. We estimated LTL from blood-derived whole-genome sequences in the All of Us research program (n = 242,494) with diverse ancestries across the USA. LTL was associated with lifestyle, socioeconomic status, biomarkers, cardiometabolic diseases and neoplasms, with heterogeneity across genetic ancestries and sexes. Geographical analysis revealed that significantly longer LTL clustered in the West Coast and Central Midwest, while significantly shorter LTL clustered in the Southeast in the USA. Genome-wide association studies and meta-analyses with the UK Biobank (n = 679,972) found 234 nonoverlapping loci, of which 37 were novel. We identified six novel loci unique to non-European-like populations and one specific to women. Rare variant analysis uncovered nine novel genes, providing new functional insights. Our study highlighted underappreciated contextual heterogeneities of phenomic and genomic associations with LTL. Analyses of leukocyte telomere length in All of Us identify associations with various lifestyle, socioeconomic and disease traits. Genome-wide analyses combining All of Us with UK Biobank data discover new loci contributing to telomere length variation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"831-840"},"PeriodicalIF":29.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02567-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531081","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":"Strand-seq and the future of personalized genomics","authors":"Vincent C. T. Hanlon, Peter M. Lansdorp","doi":"10.1038/s41588-026-02548-4","DOIUrl":"https://doi.org/10.1038/s41588-026-02548-4","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"14 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506814","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 refined blueprint for human skin","authors":"Maria Luiza Lopes De Oliveira, Piotr Konieczny","doi":"10.1038/s41588-026-02555-5","DOIUrl":"10.1038/s41588-026-02555-5","url":null,"abstract":"Bu using organ-wide single-cell MERFISH, researchers create a spatial atlas of healthy human skin and identify distinct site-specific cellular compositions. This work emphasize the importance of skin organization, from molecular architecture to anatomical scales, in maintaining skin homeostasis and influencing patterns of disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"679-680"},"PeriodicalIF":29.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502241","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}