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Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma (vol 33, pg 2429, 2019)

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LEUKEMIA 2020年第5期34卷 1485-1485页

作者： Harrington, Colleen T. Sotillo, Elena Robert, Aude Hayer, Katharina E. Bogusz, Agata M. Psathas, James Yu, Duonan Taylor, Deanne Dang, Chi V. Klein, Peter S. Hogarty, Michael D. Geoerger, Birgit El-Deiry, Wafik S. Wiels, Joelle Thomas-Tikhonenko, Andrei Division of Cancer Pathobiology Children’s Hospital of Philadelphia Philadelphia USA Cell & Molecular Biology Graduate Group Perelman School of Medicine at the University of Pennsylvania Philadelphia USA Stanford Cancer Institute Stanford USA CNRS UMR 8126 Univ Paris-Sud - Université Paris-Saclay Institut Gustave Roussy Villejuif France Department of Biomedical and Health Informatics Children’s Hospital of Philadelphia Philadelphia USA Department of Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia USA The Janssen Pharmaceutical Companies of Johnson & Johnson Malvern USA Noncoding RNA Center Yangzhou University Yangzhou China Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelphia USA Molecular and Cellular Oncogenesis Program The Wistar Institute Philadelphia USA Department of Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia USA Division of Oncology Children’s Hospital of Philadelphia Philadelphia USA CNRS UMR 8203 Univ Paris-Sud - Université Paris-Saclay Institut Gustave Roussy Villejuif France Department of Pediatric and Adolescent Oncology Univ Paris-Sud - Université Paris-Saclay Institut Gustave Roussy Villejuif France Department of Pathology and Laboratory Medicine Brown University Medical School Providence USA

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic

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四川生理科学杂志 2022年第7期44卷 1246-1246页

作者： Michael Worobey Department of Ecology and Evolutionary Biology University of Arizona Tucson AZ 85721 USA Department of Immunology and Microbiology The Scripps Research Institute La Jolla CA 92037 USA W. Harry Feinstone Department of Molecular Microbiology and Immunology Johns Hopkins Bloomberg School of Public Health Baltimore MD 21205 USA Bioinformatics and Systems Biology Graduate Program University of California San Diego La Jolla CA 92093 USA Department of Biomedical Informatics University of California San Diego La Jolla CA 92093 USA Department of Human Genetics University of Utah School of Medicine Salt Lake City UT 84112 USA Vaccine and Infectious Disease Organization University of Saskatchewan Saskatoon SK S7N 5E3 Canada Center for Global Health Science and Security Georgetown University Washington DC 20057 USA Department of Zoology University of Oxford Oxford OX1 3SZ UK Wildlife Conservation Research Unit Department of Zoology The Recanati-Kaplan Centre University of Oxford Oxford OX13 5QL UK Pandemic and Disaster Preparedness Centre Erasmus University Medical Center 3015 CE Rotterdam Netherlands Department of Viroscience Erasmus University Medical Center 3015 CE Rotterdam Netherlands Department of Biostatistics Fielding School of Public Health University of California Los Angeles Los Angeles CA 90095 USA Department of Human Genetics David Geffen School of Medicine University of California Los Angeles Los Angeles CA 90095 USA Department of Computational Medicine David Geffen School of Medicine University of California Los Angeles Los Angeles CA 90095 USA Department of Medicine University of California San Diego La Jolla CA 92093 USA Department of Microbiology Immunology and Transplantation Rega Institute for Medical Research KU Leuven 3000 Leuven Belgium Global Virus Network (GVN) Baltimore MD 21201 USA MRC-University of Glasgow Center for Virus Research Glasgow G61 1QH UK Tulane University School of Medicine Department of Microbiology and Immu

Understanding how severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged in 2019 is critical to preventing zoonotic outbreaks before they become the next *** Huanan Seafood Wholesale Market in Wuhan,China,was identified as a likely source of cases in early reports but later this conclusion became *** show the earliest known COVID-19 cases from December 2019,including those without reported direct links,were geographically centered on this *** report that live SARS-CoV-2 susceptible mammals were sold at the market in late 2019 and,within the market,SARS-CoV-2-positive environmental samples were spatially associated with vendors selling live mammals.

关键词： Market likely Wuhan

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Patterns of somatic structural variation in human cancer genomes (vol 578, pg 112, 2020)

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NATURE 2023年第7948期614卷 E38-E38页

作者： Li, Yilong Roberts, Nicola D. Wala, Jeremiah A. Shapira, Ofer Schumacher, Steven E. Kumar, Kiran Khurana, Ekta Waszak, Sebastian Korbel, Jan O. Haber, James E. Imielinski, Marcin Weischenfeldt, Joachim Beroukhim, Rameen Campbell, Peter J. Cancer Genome Project Wellcome Trust Sanger Institute Hinxton UK Totient Inc Cambridge MA USA Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Department of Haematology University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Korea Advanced Institute of Science and Technology Daejeon South Korea Department of Zoology Genetics and Physical Anthropology University of Santiago de Compostela Santiago de Compostela Spain Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS) University of Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) University of Vigo Vigo Spain Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain Department of Zoology Genetics and Physical Anthropology (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) Universidade de Vigo Vigo Spain The Broad Institute of Harvard and MIT Cambridge MA USA Bioinformatics and Integrative Genomics Harvard University Cambridge MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Broad Institute of MIT and Harvard Cambridge MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Harvard Medical School Boston MA USA Massachusetts General Hospital Center for Cancer Research Charlestown MA USA Dana-Farber Cancer Institute Boston MA USA Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute and Harvard Medical School Boston MA USA Weill Cornell Medical College New York NY USA Department of Physiology and Biophysics Weill Cornell Medicine New York NY USA Institute for Computational Biomedicine Weill Cornell Medicine New York NY USA Controlled Department and Institution New York NY USA Englander Institute for Precision Medicine Weill Cornell Medicine Ne

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Genomic basis for RNA alterations in cancer (vol 578, pg 129, 2020)

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NATURE 2023年第7948期614卷 E37-E37页

作者： Calabrese, Claudia Davidson, Natalie R. Demircioglu, Deniz Fonseca, Nuno A. He, Yao Lehmann, Kjong-Van Liu, Fenglin Shiraishi, Yuichi Soulette, Cameron M. Urban, Lara Greger, Liliana Li, Siliang Liu, Dongbing Perry, Marc D. Xiang, Qian Zhang, Fan Zhang, Junjun Bailey, Peter Erkek, Serap Hoadley, Katherine A. Hou, Yong Huska, Matthew R. Kilpinen, Helena Korbel, Jan O. Marin, Maximillian G. Markowski, Julia Nandi, Tannistha Pan-Hammarstrom, Qiang Pedamallu, Chandra Sekhar Siebert, Reiner Stark, Stefan G. Su, Hong Tan, Patrick Waszak, Sebastian M. Yung, Christina Zhu, Shida Awadalla, Philip Creighton, Chad J. Meyerson, Matthew Ouellette, B. F. Francis Wu, Kui Yang, Huanming Brazma, Alvis Brooks, Angela N. Goke, Jonathan Ratsch, Gunnar Schwarz, Roland F. Stegle, Oliver Zhang, Zemin European Molecular Biology Laboratory European Bioinformatics Institute Hinxton UK European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Cambridge UK Genome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg Germany CIBIO/InBIO - Research Center in Biodiversity and Genetic Resources Universidade do Porto Vairão Portugal Berlin Institute for Medical Systems Biology Max Delbruck Center for Molecular Medicine Berlin Germany German Cancer Consortium (DKTK) partner site Berlin Germany German Cancer Research Center (DKFZ) Heidelberg Germany Berlin Institute for Medical Systems Biology Max Delbrück Center for Molecular Medicine Berlin Germany German Cancer Consortium (DKTK) Partner site Berlin Berlin Germany European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany Division of Computational Genomics and Systems Genetics German Cancer Research Center (DKFZ) Heidelberg Germany ETH Zurich Zurich Switzerland Memorial Sloan Kettering Cancer Center New York NY USA Weill Cornell Medical College New York NY USA SIB Swiss Institute of Bioinformatics Lausanne Switzerland University Hospital Zurich Zurich Switzerland Computational Biology Center Memorial Sloan Kettering Cancer Center New York NY USA Department of Biology ETH Zurich Zürich Switzerland Department of Computer Science ETH Zurich Zurich Switzerland Korea University Seoul South Korea Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York NY USA Department of Physiology and Biophysics Weill Cornell Medicine New York NY USA Institute for Computational Biomedicine Weill Cornell Medicine New York NY USA Controlled Department and Institution New York NY USA Englander Institute for Precision Medicine Weill Cornell Medicine New York NY USA National University of Singapore Singapore Singapore Genome Institute of Singapore Singapore Singapore Computational and Systems Biology Genome Institute of Singap

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Geographic and age variations in mutational processes in colorectal cancer

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Nature 2025年 1-11页

作者： Marcos Díaz-Gay Mariya Kazachkova Ammal Abbasi Christopher D. Steele Raviteja Vangara Erik N. Bergstrom Azhar Khandekar Burçak Otlu Ludmil B. Alexandrov Wellington dos Santos Sergey Senkin Behnoush Abedi-Ardekani Ana Carolina de Carvalho Thomas Cattiaux Ricardo Cortez Cardoso Penha Valérie Gaborieau Priscilia Chopard Sandra Perdomo Paul Brennan Sarah Moody Jingwei Wang Stephen Fitzgerald Saamin Cheema Calli Latimer Jon W. Teague Laura Humphreys Michael R. Stratton Christine Carreira Anush Mukeriya David Zaridze Riley Cox Monique Albert Larry Phouthavongsy Steven Gallinger Reza Malekzadeh Ahmadreza Niavarani Marko Miladinov Katarina Erić Sasa Milosavljevic Suleeporn Sangrajrang Maria Paula Curado Samuel Aguiar Rui Manuel Reis Monise Tadin Reis Luis Gustavo Romagnolo Denise Peixoto Guimarães Ivana Holcatova Jaroslav Kalvach Carlos Alberto Vaccaro Tamara Alejandra Piñero Beata Świątkowska Jolanta Lissowska Katarzyna Roszkowska-Purska Antonio Huertas-Salgado Tatsuhiro Shibata Satoshi Shiba Surasak Sangkhathat Taned Chitapanarux Gholamreza Roshandel Patricia Ashton-Prolla Daniel C. Damin Francine Hehn de Oliveira Trevor D. Lawley Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA Department of Bioengineering University of California San Diego La Jolla CA USA Moores Cancer Center University of California San Diego La Jolla CA USA Digital Genomics Group Structural Biology Program Spanish National Cancer Research Center (CNIO) Madrid Spain Biomedical Sciences Graduate Program University of California San Diego La Jolla CA USA Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA Department of Health Informatics Graduate School of Informatics Middle East Technical University Ankara Turkey Sanford Stem Cell Institute University of California San Diego La Jolla CA USA Genomic Epidemiology Branch International Agency for Research on Cancer (IARC/WHO) Lyon France Cancer Ageing and Somatic Mutation Wellcome Sanger Institute Cambridge UK Evidence Synthesis and Classification Branch International Agency for Research on Cancer (IARC/WHO) Lyon France Clinical Epidemiology N. N. Blokhin National Medical Research Centre of Oncology Moscow Russia Ontario Tumour Bank Ontario Institute for Cancer Research Toronto Ontario Canada Centre for Biodiversity Genomics University of Guelph Guelph Ontario Canada Lunenfeld-Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada Digestive Oncology Research Center Digestive Disease Research Institute Tehran University of Medical Sciences Tehran Iran Clinic for Digestive Surgery—First Surgical Clinic University Clinical Centre of Serbia Belgrade Serbia Department of Pathology University Clinical Centre of Serbia Belgrade Serbia International Organization for Cancer Prevention and Research Belgrade Serbia National Cancer Institute Bangkok Thailand Department of Epidemiology A. C. Camargo Cancer Center Sao Paulo Brazil Colon Cancer Reference Center A. C. Camargo Cancer Center Sao Paulo Brazil Molecular Oncology Research Center Barretos Cancer Hospital

Incidence rates of colorectal cancer vary geographically and have changed over time1. Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries2,3,4,5. The reasons for this increase are unknown. Here we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite-unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown aetiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin6,7, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked toAPCdriver mutations, with ID18 being responsible for about 25% ofAPCdriver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.

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The repertoire of mutational signatures in human cancer (vol 578, pg 94, 2020)

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NATURE 2023年第7948期614卷 E41-E41页

作者： Alexandrov, Ludmil B. Kim, Jaegil Haradhvala, Nicholas J. Huang, Mi Ni Ng, Alvin Wei Tian Wu, Yang Boot, Arnoud Covington, Kyle R. Gordenin, Dmitry A. Bergstrom, Erik N. Islam, S. M. Ashiqul Lopez-Bigas, Nuria Klimczak, Leszek J. McPherson, John R. Morganella, Sandro Sabarinathan, Radhakrishnan Wheeler, David A. Mustonen, Ville Getz, Gad Rozen, Steven G. Stratton, Michael R. Department of Cellular and Molecular Medicine Department of Bioengineering Moores Cancer Center University of California San Diego CA USA Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Department of Cellular and Molecular Medicine and Department of Bioengineering University of California San Diego La Jolla CA USA UC San Diego Moores Cancer Center San Diego CA USA University of California San Diego San Diego CA USA Broad Institute of MIT and Harvard Cambridge MA USA Center for Cancer Research Massachusetts General Hospital Boston MA USA Massachusetts General Hospital Boston MA USA Department of Pathology Massachusetts General Hospital Boston MA USA Harvard Medical School Boston MA USA Laboratory for Medical Science Mathematics RIKEN Center for Integrative Medical Sciences Yokohama Japan Computational Biology Program Ontario Institute for Cancer Research Toronto ON Canada Programme in Cancer & Stem Cell Biology Duke-NUS Medical School Singapore Singapore Centre for Computational Biology Duke-NUS Medical School Singapore Singapore Programme in Cancer and Stem Cell Biology Duke-NUS Medical School Singapore Singapore Programme in Cancer and Stem Cell Biology Centre for Computational Biology Duke-NUS Medical School Singapore Singapore SingHealth Duke-NUS Institute of Precision Medicine National Heart Centre Singapore Singapore Singapore Cancer Science Institute of Singapore National University of Singapore Singapore Singapore Institute of Molecular and Cell Biology Singapore Singapore Laboratory of Cancer Epigenome Division of Medical Science National Cancer Centre Singapore Singapore Singapore Duke-NUS Medical School Singapore Singapore Human Genome Sequencing Center Baylor College of Medicine Houston TX USA Dan L. Duncan Cancer Center Baylor College of Medicine Houston TX USA Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA Genome Integrity and Structural Biology Laboratory National Ins

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Validation of MRI-VLFF for the non-invasive measurement of steatosis in children

GastroHep

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GastroHep 2020年第4期2卷

作者： Miriam B. Vos Eduardo Castillo-Leon Jack Knight-Scott Rebecca Cleeton Alvin Jay Freeman Jennifer K. Frediani Albert Hernandez Stephen F. Simoneaux Jun Kong Alton Brad Farris Michael J House Tim St. Pierre Division of Gastroenterology Hepatology and Nutrition Department of Pediatrics Emory University Atlanta GA USA Children's Healthcare of Atlanta Atlanta GA USA Nutrition and Health Sciences Program Laney Graduate School Emory University Atlanta GA USA Department of Radiology Children's Healthcare of Atlanta Atlanta GA USA Department of Computer Science and Biomedical Informatics Emory University Atlanta GA USA Department of Mathematics and Statistics and Computer Science Georgia State University Atlanta GA USA Department of Pathology and Laboratory Medicine Emory University Atlanta GA USA School of Physics Mathematics and Computing The University of Western Australia Crawley WA Australia Resonance Health Ltd Claremont WA Australia

Background & Aims Magnetic resonance-based steatosis measurement of the liver has become the non-invasive gold standard; however very few diagnostic thresholds have been independently validated and none in children. This study was designed to validate diagnostic thresholds, assess repeatability and the relationship to histology of a proprietary MRI volumetric liver fat fraction (VLFF) method (HepaFat-Scan ® ) and magnetic resonance spectroscopy (MRS) proton density fat fraction (PDFF) method. Methods This cross-sectional study assesses the diagnostic accuracy of MRI-VLFF and MRS-PDFF of 50 children who had a clinically indicated liver biopsy. Twenty-five children were randomly selected for intra-examination repeatability. The positive pixel count (PPC) algorithm was used to quantify the area of fat vesicles in the histology. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnostic accuracy. Bland-Altman plots were used to compare the methods and examine the repeatability. Results The MRI-VLFF ranged from 0.3% to 35.4% and the MRS-PDFF ranged from 0.5% to 36.9%. Based on histopathological analysis, the diagnostic accuracy of MRI-VLFF for steatosis detection (grade 0 vs 1-3) showed an AUROC of 0.95 (95% confidence interval [CI]: 0.89-1.00), whereas MRI-PDFF classified grade 0 vs 1-3 showed an AUROC of 0.96 (95% CI: 0.91-1.00). The repeatability coefficients were 1.8 (±0.5) % for MRI-VLFF and 2.1 (±0.6) % for MRS-PDFF. There was no bias between MRI-VLFF and PPC steatosis. To allow direct comparison, MRS-PDFF was converted to MRS-VLFF. Small, but significant biases were measured between PPC steatosis and MRS-VLFF (−1.38%) and between MRI-VLFF and MRS-VLFF (−1.39%). Conclusions Both MRI-VLFF and MRS-PDFF accurately estimated hepatic steatosis in children with excellent agreement with the histological assessment.

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GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

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Nature genetics 2023年第9期55卷 1471-1482页

作者： Remi Stevelink Dorothee Kasteleijn-Nolst Trenite Bobby P. C. Koeleman Dick Lindhout Anja C. M. Sonsma Ciarán Campbell Gianpiero L. Cavalleri Norman Delanty Hany El-Naggar Austin Lacey Peter Widdess-Walsh Colin P. Doherty Siwei Chen Claire Churchhouse Mark J. Daly Yen-Chen A. Feng Daniel P. Howrigan Mitja I. Kurki Benjamin M. Neale Aarno Palotie Wei Zhou Namrata Gupta Henrike O. Heyne Bassel Abou-Khalil Kevin F. Haas R. S. Taneja Oluyomi M. Adesoji Michael Nothnagel Peter Nürnberg Thomas Sander Zaid Afawi Ilan Blatt Amos D. Korczyn Elisabetta Amadori Ganna Balagura Antonella Riva Marcello Scala Paolo Scudieri Pasquale Striano Federico Zara Michele Iacomino Francesca Madia Alison Anderson Patrick Kwan Terence J. O’Brien Slavé Petrovski K. Meng Tan Marian Todaro Joseph Anderson Danielle M. Andrade Quratulain Zulfiqar Ali Grazia Annesi Pauls Auce Andreja Avbersek Simona Balestrini Vera Braatz Claudia B. Catarino Krishna Chinthapalli Jennifer Jamnadas-Khoda Dalia Kasperavičiūte Costin Leu Josemir W. Sander Sanjay M. Sisodiya Sara Zagaglia Melanie Bahlo Karen L. Oliver Mark D. Baker Beata Fonferko-Shadrach William O. Pickrell Carmen Barba Claudia Bianchini Viola Doccini Renzo Guerrini Davide Mei Martino Montomoli Elena Parrini Annalisa Vetro Karen Barboza Fabrice Bartolomei Thomas Bast Bernhard J. Steinhoff Larry Baum Stacey S. Cherny Pak Sham Tobias Baumgartner Christian E. Elger Kerstin Hallmann Wolfram S. Kunz Rainer Surges Randi von Wrede Gábor Zsurka Betül Baykan Nerses Bebek Yeşim Kesim Albert J. Becker Susanne Schoch Felicitas Becker Caitlin A. Bennett Samuel F. Berkovic Stephanie L. Leech Brigid M. Regan Ingrid E. Scheffer Bianca Berghuis Ahmad Beydoun Wassim Nasreddine Francesca Bisulli Lidia Di Vito Lorenzo Ferri Tania Giangregorio Laura Licchetta Raffaella Minardi Barbara Mostacci Carlotta Stipa Paolo Tinuper Lorenzo Muccioli Federica Pondrelli Dheeraj R. Bobbili Emadeldin Hassanin Roland Krause Zied Landoulsi Patrick May Ingo Borggraefe Christian Bosselmann Christian Hengsbach Josua Kegele Stephen Lauxmann Department of Genetics University Medical Center Utrecht Utrecht The Netherlands Stichting Epilepsie Instellingen Nederland (SEIN) Heemstede The Netherlands School of Pharmacy and Biomolecular Sciences The Royal College of Surgeons in Ireland Dublin Ireland The FutureNeuro Research Centre Dublin Ireland Department of Neurology Beaumont Hospital Dublin Ireland Department of Neurology St. James’s Hospital Dublin Ireland Analytic and Translational Genetics Unit Department of Medicine Massachusetts General Hospital and Harvard Medical School Boston MA USA Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA Stanley Center for Psychiatric Research Broad Institute of Harvard and M.I.T Cambridge MA USA Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland Psychiatric & Neurodevelopmental Genetics Unit Department of Psychiatry Massachusetts General Hospital and Harvard Medical School Boston MA USA Division of Biostatistics Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan Hasso Plattner Institute Digital Health Center University of Potsdam Potsdam Germany Hasso Plattner Institute Mount Sinai School of Medicine New York City NY USA Department of Neurology Vanderbilt University Medical Center Nashville TN USA Cologne Center for Genomics (CCG) University of Cologne Faculty of Medicine and University Hospital Cologne Cologne Germany University Hospital Cologne Cologne Germany Department of Neurology Charité Universitaetsmedizin Berlin Campus Virchow-Clinic Berlin Germany Tel-Aviv University Sackler Faculty of Medicine Ramat Aviv Israel Department of Neurology Sheba Medical Center Ramat Gan Israel Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genova Genova Italy IRCCS Istituto Giannina Gaslini Genova Italy Department of Medicine University of Melbour

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

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The evolutionary history of 2,658 cancers (vol 578, pg 122, 2020)

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NATURE 2023年第7948期614卷 E42-E42页

作者： Gerstung, Moritz Jolly, Clemency Leshchiner, Ignaty Dentro, Stefan C. Gonzalez, Santiago Rosebrock, Daniel Mitchell, Thomas J. Rubanova, Yulia Anur, Pavana Yu, Kaixian Tarabichi, Maxime Deshwar, Amit Wintersinger, Jeff Kleinheinz, Kortine Vazquez-Garcia, Ignacio Haase, Kerstin Jerman, Lara Sengupta, Subhajit Macintyre, Geoff Malikic, Salem Donmez, Nilgun Livitz, Dimitri G. Cmero, Marek Demeulemeester, Jonas Schumacher, Steven Fan, Yu Yao, Xiaotong Lee, Juhee Schlesner, Matthias Boutros, Paul C. Bowtell, David D. Zhu, Hongtu Getz, Gad Imielinski, Marcin Beroukhim, Rameen Sahinalp, S. Cenk Ji, Yuan Peifer, Martin Markowetz, Florian Mustonen, Ville Yuan, Ke Wang, Wenyi Morris, Quaid D. Spellman, Paul T. Wedge, David C. Van Loo, Peter European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Cambridge UK European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany Wellcome Sanger Institute Cambridge UK Genome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg Germany University of Ljubljana Ljubljana Slovenia The Francis Crick Institute London UK Big Data Institute University of Oxford Oxford UK Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Big Data Institute Li Ka Shing Centre University of Oxford Oxford UK University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Department of Applied Mathematics and Theoretical Physics Centre for Mathematical Sciences University of Cambridge Cambridge UK Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA Department of Statistics Columbia University New York NY USA Department of Haematology University of Cambridge Cambridge UK University of Leuven Leuven Belgium Broad Institute of MIT and Harvard Cambridge MA USA Center for Cancer Research Massachusetts General Hospital Charlestown MA USA Department of Pathology Massachusetts General Hospital Boston MA USA Harvard Medical School Boston MA USA Center for Cancer Research Massachusetts General Hospital Boston MA USA Dana-Farber Cancer Institute Boston MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Oxford NIHR Biomedical Research Centre Oxford UK Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK University of Toronto Toronto Ontario Canada Vector Institute Toronto Ontario Canada Vector Institute Toronto ON Canada Department of Computer Science University of Toronto Toronto ON Canada Ontario Institute for Cancer Research Toronto Ontario Canada University of California Los Angeles

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Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

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Nature 2024年第8003期627卷 347-357页

作者： Ken Suzuki Konstantinos Hatzikotoulas Lorraine Southam Henry J Taylor Xianyong Yin Kim M Lorenz Ravi Mandla Alicia Huerta-Chagoya Giorgio E M Melloni Stavroula Kanoni Nigel W Rayner Ozvan Bocher Ana Luiza Arruda Kyuto Sonehara Shinichi Namba Simon S K Lee Michael H Preuss Lauren E Petty Philip Schroeder Brett Vanderwerff Mart Kals Fiona Bragg Kuang Lin Xiuqing Guo Weihua Zhang Jie Yao Young Jin Kim Mariaelisa Graff Fumihiko Takeuchi Jana Nano Amel Lamri Masahiro Nakatochi Sanghoon Moon Robert A Scott James P Cook Jung-Jin Lee Ian Pan Daniel Taliun Esteban J Parra Jin-Fang Chai Lawrence F Bielak Yasuharu Tabara Yang Hai Gudmar Thorleifsson Niels Grarup Tamar Sofer Matthias Wuttke Chloé Sarnowski Christian Gieger Darryl Nousome Stella Trompet Soo-Heon Kwak Jirong Long Meng Sun Lin Tong Wei-Min Chen Suraj S Nongmaithem Raymond Noordam Victor J Y Lim Claudia H T Tam Yoonjung Yoonie Joo Chien-Hsiun Chen Laura M Raffield Bram Peter Prins Aude Nicolas Lisa R Yanek Guanjie Chen Jennifer A Brody Edmond Kabagambe Ping An Anny H Xiang Hyeok Sun Choi Brian E Cade Jingyi Tan K Alaine Broadaway Alice Williamson Zoha Kamali Jinrui Cui Manonanthini Thangam Linda S Adair Adebowale Adeyemo Carlos A Aguilar-Salinas Tarunveer S Ahluwalia Sonia S Anand Alain Bertoni Jette Bork-Jensen Ivan Brandslund Thomas A Buchanan Charles F Burant Adam S Butterworth Mickaël Canouil Juliana C N Chan Li-Ching Chang Miao-Li Chee Ji Chen Shyh-Huei Chen Yuan-Tsong Chen Zhengming Chen Lee-Ming Chuang Mary Cushman John Danesh Swapan K Das H Janaka de Silva George Dedoussis Latchezar Dimitrov Ayo P Doumatey Shufa Du Qing Duan Kai-Uwe Eckardt Leslie S Emery Daniel S Evans Michele K Evans Krista Fischer James S Floyd Ian Ford Oscar H Franco Timothy M Frayling Barry I Freedman Pauline Genter Hertzel C Gerstein Vilmantas Giedraitis Clicerio González-Villalpando Maria Elena González-Villalpando Penny Gordon-Larsen Myron Gross Lindsay A Guare Sophie Hackinger Liisa Hakaste Sohee Han Andrew T Hattersley Christian Herder Momoko Horikoshi Annie-Green Howard Willa Centre for Genetics and Genomics Versus Arthritis Centre for Musculoskeletal Research Division of Musculoskeletal and Dermatological Sciences University of Manchester Manchester UK. Department of Diabetes and Metabolic Diseases Graduate School of Medicine University of Tokyo Tokyo Japan. Department of Statistical Genetics Osaka University Graduate School of Medicine Suita Japan. Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany. konstantinos.hatzikotoulas@helmholtz-munich.de. Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany. Center for Precision Health Research National Human Genome Research Institute National Institutes of Health Bethesda MD USA. British Heart Foundation Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Cambridge UK. Heart and Lung Research Institute University of Cambridge Cambridge UK. Department of Epidemiology School of Public Health Nanjing Medical University Nanjing China. Department of Biostatistics and Center for Statistical Genetics University of Michigan Ann Arbor MI USA. Corporal Michael J. Crescenz VA Medical Center Philadelphia PA USA. Department of Systems Pharmacology and Translational Therapeutics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA. Department of Genetics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA. Programs in Metabolism and Medical and Population Genetics Broad Institute of Harvard and MIT Cambridge MA USA. Diabetes Unit and Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. TIMI Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA. William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London L

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

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