Nature genetics最新文献

{"title":"Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification","authors":"Simone M. Haag, Shiqi Xie, Celine Eidenschenk, Jean-Philippe Fortin, Marinella Callow, Mike Costa, Aaron Lun, Chris Cox, Sunny Z. Wu, Rachana N. Pradhan, Jaclyn Lock, Julia A. Kuhn, Loryn Holokai, Minh Thai, Emily Freund, Ariane Nissenbaum, Mary Keir, Christopher J. Bohlen, Scott Martin, Kathryn Geiger-Schuller, Hussein A. Hejase, Brian L. Yaspan, Sandra Melo Carlos, Shannon J. Turley, Aditya Murthy","doi":"10.1038/s41588-024-01962-w","DOIUrl":"10.1038/s41588-024-01962-w","url":null,"abstract":"Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory ‘states’ that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity. Functional screens using mouse and human primary macrophages identify regulators of distinct inflammatory states, including a role for m6A mRNA modification in TNF production.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2493-2505"},"PeriodicalIF":31.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487082","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: Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes","authors":"Alicia Huerta-Chagoya, Philip Schroeder, Ravi Mandla, Jiang Li, Lowri Morris, Maheak Vora, Ahmed Alkanaq, Dorka Nagy, Lukasz Szczerbinski, Jesper G. S. Madsen, Silvia Bonàs-Guarch, Fanny Mollandin, Joanne B. Cole, Bianca Porneala, Kenneth Westerman, Josephine H. Li, Toni I. Pollin, Jose C. Florez, Anna L. Gloyn, David J. Carey, Inês Cebola, Uyenlinh L. Mirshahi, Alisa K. Manning, Aaron Leong, Miriam Udler, Josep M. Mercader","doi":"10.1038/s41588-024-01986-2","DOIUrl":"10.1038/s41588-024-01986-2","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2576-2576"},"PeriodicalIF":31.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01986-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486678","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":"Pushing the boundaries of rare disease diagnostics with the help of the first Undiagnosed Hackathon","authors":"Angelica Maria Delgado-Vega, Helene Cederroth, Fulya Taylan, Katja Ekholm, Marlene Ek, Håkan Thonberg, Anders Jemt, Daniel Nilsson, Jesper Eisfeldt, Kristine Bilgrav Saether, Ida Höijer, Ozlem Akgun-Dogan, Yui Asano, Tahsin Stefan Barakat, Dominyka Batkovskyte, Gareth Baynam, Olaf Bodamer, Wanna Chetruengchai, Pádraic Corcoran, Madeline Couse, Daniel Danis, German Demidov, Eisuke Dohi, Mattias Erhardsson, Luis Fernandez-Luna, Toyofumi Fujiwara, Neha Garg, Roberto Giugliani, Claudia Gonzaga-Jauregui, Giedre Grigelioniene, Tudor Groza, Cecilia Gunnarsson, Anna Hammarsjö, Charles Kumi Hammond, Özden Hatirnaz Ng, Sirisha Hesketh, Dineshani Hettiarachchi, Maria Johansson Soller, Umn Ahmed Kirmani, Martin Kjellberg, Malin Kvarnung, Oleg Kvlividze, Kristina Lagerstedt-Robinson, Paul Lasko, Timo Lassmann, Lynette Y. S. Lau, Steven Laurie, Weng Khong Lim, Zhandong Liu, Mariya Lysenkova Wiklander, Prince Makay, Alassane Baneye Maiga, Carolina Maya-González, M. Stephen Meyn, Ramprasad Neethiraj, Vincenzo Nigro, Felix Nordgren, Jessica Nordlund, Sara Orrsjö, Jesper Ottosson, Ugur Ozbek, Özkan Özdemir, Clyde Partin, David A. Pearce, Raquel Peck, Annie Pedersen, Maria Pettersson, Monnat Pongpanich, Manuel Posada de la Paz, Arun Ramani, Juan Andres Romero, Vanessa I. Romero, Richard Rosenquist, Aung Min Saw, Matthew Spencer, Eva-Lena Stattin, Chalurmpon Srichomthong, Isabel Tapia-Paez, Domenica Taruscio, Julie P. Taylor, Tinatin Tkemaladze, Ian Tully, Zeynep Tümer, Wendy A. G. van Zelst-Stams, Alain Verloes, Emma Västerviga, Sailan Wang, Rachel Yang, Shinya Yamamoto, Vicente A. Yépez, Qing Zhang, Vorasuk Shotelersuk, Samuel Agyei Wiafe, Yasemin Alanay, Lorenzo D. Botto, Salman Kirmani, Aimé Lumaka, Elizabeth Emma Palmer, Ratna Dua Puri, Valtteri Wirta, Anna Lindstrand, Orion J. Buske, Mikk Cederroth, Ann Nordgren","doi":"10.1038/s41588-024-01941-1","DOIUrl":"10.1038/s41588-024-01941-1","url":null,"abstract":"In the first-ever Undiagnosed Hackathon, nearly 100 experts from 28 countries combined advanced phenotyping and genomic techniques for 48 hours, ultimately providing diagnoses to 40% of the previously undiagnosed families. This inspiring model demonstrates the power of multidisciplinary collaboration and patient partnership in precision diagnostics.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2287-2294"},"PeriodicalIF":31.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451819","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":"Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries","authors":"Luis M. García-Marín, Adrian I. Campos, Santiago Diaz-Torres, Jill A. Rabinowitz, Zuriel Ceja, Brittany L. Mitchell, Katrina L. Grasby, Jackson G. Thorp, Ingrid Agartz, Saud Alhusaini, David Ames, Philippe Amouyel, Ole A. Andreassen, Konstantinos Arfanakis, Alejandro Arias-Vasquez, Nicola J. Armstrong, Lavinia Athanasiu, Mark E. Bastin, Alexa S. Beiser, David A. Bennett, Joshua C. Bis, Marco P. M. Boks, Dorret I. Boomsma, Henry Brodaty, Rachel M. Brouwer, Jan K. Buitelaar, Ralph Burkhardt, Wiepke Cahn, Vince D. Calhoun, Owen T. Carmichael, Mallar Chakravarty, Qiang Chen, Christopher R. K. Ching, Sven Cichon, Benedicto Crespo-Facorro, Fabrice Crivello, Anders M. Dale, George Davey Smith, Eco J. C. de Geus, Philip L. De Jager, Greig I. de Zubicaray, Stéphanie Debette, Charles DeCarli, Chantal Depondt, Sylvane Desrivières, Srdjan Djurovic, Stefan Ehrlich, Susanne Erk, Thomas Espeseth, Guillén Fernández, Irina Filippi, Simon E. Fisher, Debra A. Fleischman, Evan Fletcher, Myriam Fornage, Andreas J. Forstner, Clyde Francks, Barbara Franke, Tian Ge, Aaron L. Goldman, Hans J. Grabe, Robert C. Green, Oliver Grimm, Nynke A. Groenewold, Oliver Gruber, Vilmundur Gudnason, Asta K. Håberg, Unn K. Haukvik, Andreas Heinz, Derrek P. Hibar, Saima Hilal, Jayandra J. Himali, Beng-Choon Ho, David F. Hoehn, Pieter J. Hoekstra, Edith Hofer, Wolfgang Hoffmann, Avram J. Holmes, Georg Homuth, Norbert Hosten, M. Kamran Ikram, Jonathan C. Ipser, Clifford R. Jack Jr, Neda Jahanshad, Erik G. Jönsson, Rene S. Kahn, Ryota Kanai, Marieke Klein, Maria J. Knol, Lenore J. Launer, Stephen M. Lawrie, Stephanie Le Hellard, Phil H. Lee, Hervé Lemaître, Shuo Li, David C. M. Liewald, Honghuang Lin, W. T. Longstreth Jr, Oscar L. Lopez, Michelle Luciano, Pauline Maillard, Andre F. Marquand, Nicholas G. Martin, Jean-Luc Martinot, Karen A. Mather, Venkata S. Mattay, Katie L. McMahon, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Nazanin Mirza-Schreiber, Yuri Milaneschi, Thomas H. Mosley, Thomas W. Mühleisen, Bertram Müller-Myhsok, Susana Muñoz Maniega, Matthias Nauck, Kwangsik Nho, Wiro J. Niessen, Markus M. Nöthen, Paul A. Nyquist, Jaap Oosterlaan, Massimo Pandolfo, Tomas Paus, Zdenka Pausova, Brenda W. J. H. Penninx, G. Bruce Pike, Bruce M. Psaty, Benno Pütz, Simone Reppermund, Marcella D. Rietschel, Shannon L. Risacher, Nina Romanczuk-Seiferth, Rafael Romero-Garcia, Gennady V. Roshchupkin, Jerome I. Rotter, Perminder S. Sachdev, Philipp G. Sämann, Arvin Saremi, Muralidharan Sargurupremraj, Andrew J. Saykin, Lianne Schmaal, Helena Schmidt, Reinhold Schmidt, Peter R. Schofield, Markus Scholz, Gunter Schumann, Emanuel Schwarz, Li Shen, Jean Shin, Sanjay M. Sisodiya, Albert V. Smith, Jordan W. Smoller, Hilkka S. Soininen, Vidar M. Steen, Dan J. Stein, Jason L. Stein, Sophia I. Thomopoulos, Arthur W. Toga, Diana Tordesillas-Gutiérrez, Julian N. Trollor, Maria C. Valdes-Hernandez, Dennis van ′t Ent, Hans van Bokhoven, Dennis van der Meer, Nic J. A. van der Wee, Javier Vázquez-Bourgon, Dick J. Veltman, Meike W. Vernooij, Arno Villringer, Louis N. Vinke, Henry Völzke, Henrik Walter, Joanna M. Wardlaw, Daniel R. Weinberger, Michael W. Weiner, Wei Wen, Lars T. Westlye, Eric Westman, Tonya White, A. Veronica Witte, Christiane Wolf, Jingyun Yang, Marcel P. Zwiers, M. Arfan Ikram, Sudha Seshadri, Paul M. Thompson, Claudia L. Satizabal, Sarah E. Medland, Miguel E. Rentería","doi":"10.1038/s41588-024-01951-z","DOIUrl":"10.1038/s41588-024-01951-z","url":null,"abstract":"Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases. Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2333-2344"},"PeriodicalIF":31.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451818","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":"Haplotype-resolved genome assembly and resequencing analysis provide insights into genome evolution and allelic imbalance in Pinus densiflora","authors":"Min-Jeong Jang, Hye Jeong Cho, Young-Soo Park, Hye-Young Lee, Eun-Kyung Bae, Seungmee Jung, Hongshi Jin, Jongchan Woo, Eunsook Park, Seo-Jin Kim, Jin-Wook Choi, Geun Young Chae, Ji-Yoon Guk, Do Yeon Kim, Sun-Hyung Kim, Min-Jeong Kang, Hyoshin Lee, Kyeong-Seong Cheon, In Sik Kim, Yong-Min Kim, Myung-Shin Kim, Jae-Heung Ko, Kyu-Suk Kang, Doil Choi, Eung-Jun Park, Seungill Kim","doi":"10.1038/s41588-024-01944-y","DOIUrl":"10.1038/s41588-024-01944-y","url":null,"abstract":"Haplotype-level allelic characterization facilitates research on the functional, evolutionary and breeding-related features of extremely large and complex plant genomes. We report a 21.7-Gb chromosome-level haplotype-resolved assembly in Pinus densiflora. We found genome rearrangements involving translocations and inversions between chromosomes 1 and 3 of Pinus species and a proliferation of specific long terminal repeat (LTR) retrotransposons (LTR-RTs) in P. densiflora. Evolutionary analyses illustrated that tandem and LTR-RT-mediated duplications led to an increment of transcription factor (TF) genes in P. densiflora. The haplotype sequence comparison showed allelic imbalances, including presence–absence variations of genes (PAV genes) and their functional contributions to flowering and abiotic stress-related traits in P. densiflora. Allele-aware resequencing analysis revealed PAV gene diversity across P. densiflora accessions. Our study provides insights into key mechanisms underlying the evolution of genome structure, LTR-RTs and TFs within the Pinus lineage as well as allelic imbalances and diversity across P. densiflora. Chromosome-scale and haplotype-resolved assembly of Pinus densiflora sheds light on Pinus-specific genome enlargement. Comparison between haplotypes and resequencing of 30 wild accessions show allelic imbalance with roles in flowering regulation and stress resistance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2551-2561"},"PeriodicalIF":31.7,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451399","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":"Base editing screens define the genetic landscape of cancer drug resistance mechanisms","authors":"Matthew A. Coelho, Magdalena E. Strauss, Alex Watterson, Sarah Cooper, Shriram Bhosle, Giuditta Illuzzi, Emre Karakoc, Cansu Dinçer, Sara F. Vieira, Mamta Sharma, Marie Moullet, Daniela Conticelli, Jonas Koeppel, Katrina McCarten, Chiara M. Cattaneo, Vivien Veninga, Gabriele Picco, Leopold Parts, Josep V. Forment, Emile E. Voest, John C. Marioni, Andrew Bassett, Mathew J. Garnett","doi":"10.1038/s41588-024-01948-8","DOIUrl":"10.1038/s41588-024-01948-8","url":null,"abstract":"Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant that sensitizes lung cancer cells to EGFR inhibitors. Our variant-to-function map has implications for patient stratification, therapy combinations and drug scheduling in cancer treatment. Base editing screens of 11 cancer genes identify four functional classes of variants that collectively underpin sensitivity and resistance to ten commonly used drugs in cancer cell lines.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2479-2492"},"PeriodicalIF":31.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01948-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448166","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":"A regulatory network controlling developmental boundaries and meristem fates contributed to maize domestication","authors":"Zhaobin Dong, Gaoyuan Hu, Qiuyue Chen, Elena A. Shemyakina, Geeyun Chau, Clinton J. Whipple, Jennifer C. Fletcher, George Chuck","doi":"10.1038/s41588-024-01943-z","DOIUrl":"10.1038/s41588-024-01943-z","url":null,"abstract":"During domestication, early farmers selected different vegetative and reproductive traits, but identifying the causative loci has been hampered by their epistasis and functional redundancy. Using chromatin immunoprecipitation sequencing combined with genome-wide association analysis, we uncovered a developmental regulator that controls both types of trait while acting upstream of multiple domestication loci. tasselsheath4 (tsh4) is a new maize domestication gene that establishes developmental boundaries and specifies meristem fates despite not being expressed within them. TSH4 accomplishes this by using a double-negative feedback loop that targets and represses the very same microRNAs that negatively regulate it. TSH4 functions redundantly with a pair of homologs to positively regulate a suite of domestication loci while specifying the meristem that doubled seed yield in modern maize. TSH4 has a critical role in yield gain and helped generate ideal crop plant architecture, thus explaining why it was a major domestication target. Maize transcription factor TASSELSHEATH4 establishes the leaf versus meristem cell boundary and vegetative versus floral axillary meristem fates as part of a domestication gene network.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2528-2537"},"PeriodicalIF":31.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440225","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 genome-wide association analysis reveals new pathogenic pathways in gout","authors":"Tanya J. Major, Riku Takei, Hirotaka Matsuo, Megan P. Leask, Nicholas A. Sumpter, Ruth K. Topless, Yuya Shirai, Wei Wang, Murray J. Cadzow, Amanda J. Phipps-Green, Zhiqiang Li, Aichang Ji, Marilyn E. Merriman, Emily Morice, Eric E. Kelley, Wen-Hua Wei, Sally P. A. McCormick, Matthew J. Bixley, Richard J. Reynolds, Kenneth G. Saag, Tayaza Fadason, Evgenia Golovina, Justin M. O’Sullivan, Lisa K. Stamp, Nicola Dalbeth, Abhishek Abhishek, Michael Doherty, Edward Roddy, Lennart T. H. Jacobsson, Meliha C. Kapetanovic, Olle Melander, Mariano Andrés, Fernando Pérez-Ruiz, Rosa J. Torres, Timothy Radstake, Timothy L. Jansen, Matthijs Janssen, Leo A. B. Joosten, Ruiqi Liu, Orsolya I. Gaal, Tania O. Crişan, Simona Rednic, Fina Kurreeman, Tom W. J. Huizinga, René Toes, Frédéric Lioté, Pascal Richette, Thomas Bardin, Hang Korng Ea, Tristan Pascart, Geraldine M. McCarthy, Laura Helbert, Blanka Stibůrková, Anne-K. Tausche, Till Uhlig, Véronique Vitart, Thibaud S. Boutin, Caroline Hayward, Philip L. Riches, Stuart H. Ralston, Archie Campbell, Thomas M. MacDonald, FAST Study Group, Akiyoshi Nakayama, Tappei Takada, Masahiro Nakatochi, Seiko Shimizu, Yusuke Kawamura, Yu Toyoda, Hirofumi Nakaoka, Ken Yamamoto, Keitaro Matsuo, Nariyoshi Shinomiya, Kimiyoshi Ichida, Japan Gout Genomics Consortium, Chaeyoung Lee, Asia Pacific Gout Consortium, Linda A. Bradbury, Matthew A. Brown, Philip C. Robinson, Russell R. C. Buchanan, Catherine L. Hill, Susan Lester, Malcolm D. Smith, Maureen Rischmueller, Hyon K. Choi, Eli A. Stahl, Jeff N. Miner, Daniel H. Solomon, Jing Cui, Kathleen M. Giacomini, Deanna J. Brackman, Eric M. Jorgenson, GlobalGout Genetics Consortium, Hongbo Liu, Katalin Susztak, 23andMe Research Team, Suyash Shringarpure, Alexander So, Yukinori Okada, Changgui Li, Yongyong Shi, Tony R. Merriman","doi":"10.1038/s41588-024-01921-5","DOIUrl":"10.1038/s41588-024-01921-5","url":null,"abstract":"Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies. Genome-wide association analysis of gout and urate identifies 148 new loci, implicating biological pathways and prioritizing candidate genes involved in inflammatory processes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2392-2406"},"PeriodicalIF":31.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436343","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":"Parsing the spectrum of allelic architectures in diabetes","authors":"Yangxi Li, Constantin Polychronakos","doi":"10.1038/s41588-024-01950-0","DOIUrl":"10.1038/s41588-024-01950-0","url":null,"abstract":"Distinguishing ordinary diabetes from its monogenic forms has been one of the challenges in optimally managing the disease. Using high-quality imputation of rare variants and large databases, a study now defines the gray zone between the two and lays down a blueprint for objectively evaluating the related variants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2297-2298"},"PeriodicalIF":31.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430545","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":"Potential approaches to create ultimate genotypes in crops and livestock","authors":"Ben J. Hayes, Timothy J. Mahony, Kira Villiers, Christie Warburton, Kathryn E. Kemper, Eric Dinglasan, Hannah Robinson, Owen Powell, Kai Voss-Fels, Ian D. Godwin, Lee T. Hickey","doi":"10.1038/s41588-024-01942-0","DOIUrl":"10.1038/s41588-024-01942-0","url":null,"abstract":"Many thousands and, in some cases, millions of individuals from the major crop and livestock species have been genotyped and phenotyped for the purpose of genomic selection. ‘Ultimate genotypes’, in which the marker allele haplotypes with the most favorable effects on a target trait or traits in the population are combined together in silico, can be constructed from these datasets. Ultimate genotypes display up to six times the performance of the current best individuals in the population, as demonstrated for net profit in dairy cattle (incorporating a range of economic traits), yield in wheat and 100-seed weight in chickpea. However, current breeding strategies that aim to assemble ultimate genotypes through conventional crossing take many generations. As a hypothetical thought piece, here, we contemplate three future pathways for rapidly achieving ultimate genotypes: accelerated recombination with gene editing, direct editing of whole-genome haplotype sequences and synthetic biology. This Perspective discusses approaches to generate ultimate genotypes, combining the best chromosome segments in livestock and crop populations, to increase key production, sustainability and welfare traits, compared with the current best individuals.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2310-2317"},"PeriodicalIF":31.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430547","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}