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Neoantigen-augmented iPSC cancer vaccine combined with radiotherapy promotes antitumor immunity in poorly immunogenic cancers

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NPJ vaccines 2024年第1期9卷 95页

作者： Kevin Chih-Yang Huang William Tzu-Liang Chen Jia-Yi Chen Chien-Yueh Lee Chia-Hsin Wu Chia-Ying Lai Pei-Chen Yang Ji-An Liang An-Cheng Shiau K S Clifford Chao Tao-Wei Ke Department of Biomedical Imaging and Radiological Science China Medical University Taichung 406040 Taiwan ROC. chihyang0425@mail.cmu.edu.tw. Translation Research Core China Medical University Hospital China Medical University Taichung 404327 Taiwan ROC. chihyang0425@mail.cmu.edu.tw. Cancer Biology and Precision Therapeutics Center China Medical University Taichung 406040 Taiwan ROC. chihyang0425@mail.cmu.edu.tw. Department of Surgery School of Medicine China Medical University Taichung 406040 Taiwan ROC. Department of Colorectal Surgery China Medical University HsinChu Hospital China Medical University HsinChu 302 Taiwan ROC. Department of Colorectal Surgery China Medical University Hospital China Medical University Taichung 404327 Taiwan ROC. Proton Therapy and Science Center China Medical University Hospital China Medical University Taichung 404327 Taiwan ROC. Innovation Frontier Institute of Research for Science and Technology National Taipei University of Technology Taipei 106344 Taiwan ROC. Department of Electrical Engineering National Taipei University of Technology Taipei 106344 Taiwan ROC. Department of Biomedical Engineering China Medical University Taichung 406040 Taiwan ROC. Bioinformatics and Biostatistics Core Centers of Genomic and Precision Medicine National Taiwan University Taipei 10055 Taiwan ROC. Department of Biomedical Imaging and Radiological Science China Medical University Taichung 406040 Taiwan ROC. Department of Radiation Oncology China Medical University Hospital China Medical University Taichung 404327 Taiwan ROC. Department of Radiotherapy School of Medicine China Medical University Taichung 406040 Taiwan ROC. Proton Therapy and Science Center China Medical University Hospital China Medical University Taichung 404327 Taiwan ROC. d94032@mail.cmuh.org.tw. Department of Radiation Oncology China Medical University Hospital China Medical University Taichung 404327 Taiwan ROC. d94032@mail.cmuh.org.tw.

Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFNγ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.

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Author Correction: The SEQC2 epigenomics quality control (EpiQC) study

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Genome biology 2021年第1期22卷 350页

作者： Jonathan Foox Jessica Nordlund Claudia Lalancette Ting Gong Michelle Lacey Samantha Lent Bradley W Langhorst V K Chaithanya Ponnaluri Louise Williams Karthik Ramaswamy Padmanabhan Raymond Cavalcante Anders Lundmark Daniel Butler Christopher Mozsary Justin Gurvitch John M Greally Masako Suzuki Mark Menor Masaki Nasu Alicia Alonso Caroline Sheridan Andreas Scherer Stephen Bruinsma Gosia Golda Agata Muszynska Paweł P Łabaj Matthew A Campbell Frank Wos Amanda Raine Ulrika Liljedahl Tomas Axelsson Charles Wang Zhong Chen Zhaowei Yang Jing Li Xiaopeng Yang Hongwei Wang Ari Melnick Shang Guo Alexander Blume Vedran Franke Inmaculada Ibanez de Caceres Carlos Rodriguez-Antolin Rocio Rosas Justin Wade Davis Jennifer Ishii Dalila B Megherbi Wenming Xiao Will Liao Joshua Xu Huixiao Hong Baitang Ning Weida Tong Altuna Akalin Yunliang Wang Youping Deng Christopher E Mason Department of Physiology and Biophysics Weill Cornell Medicine New York NY USA. The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine Weill Cornell Medicine New York NY USA. Department of Medical Sciences and Science for Life Laboratory Uppsala University Uppsala Sweden. EATRIS ERIC- European Infrastructure for Translational Medicine De Boelelaan 1118 1081 HZ Amsterdam The Netherlands. BRCF Epigenomics Core University of Michigan Medicine Ann Arbor MI 48109 USA. Department of Quantitative Health Sciences University of Hawaii John A. Burns School of Medicine Honolulu HI 96813 USA. Tulane University New Orleans LA 70118 USA. AbbVie Genomics Research Center 1 N. Waukegan Rd North Chicago IL 60036 USA. New England Biolabs Ipswich MA 01938 USA. Albert Einstein College of Medicine Bronx NY 10461 USA. Division of Hematology/Oncology Department of Medicine Epigenomics Core Facility Weill Cornell Medicine New York NY USA. Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland. Illumina Inc Madison WI 53705 USA. Faculty of Biochemistry Biophysics and Biotechnology Jagiellonian University Krakow Poland. Małopolska Centre of Biotechnology Jagiellonian University Krakow Poland. New York Genome Center New York NY 10013 USA. Center for Genomics School of Medicine Loma Linda University Loma Linda CA 92350 USA. Department of Allergy and Clinical Immunology State Key Laboratory of Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China. Department of Neurology The Second Affiliated Hospital of Zhengzhou University Zhengzhou 450014 China. Development of Medicine the University of Chicago Chicago IL 60637 USA. Department of Neurology the Second Affiliated Hospital of Zhengzhou University Zhengzhou 450014 China. Bioinformatics and Omics Data Science Platform Berlin Institute f

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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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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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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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OTHR-04. DEVELOPMENT OF A FUNCTIONAL PLATFORM FOR REAL-TIME PERSONALIZED DRUG SENSITIVITY PROFILING OF PATIENT-DERIVED 3D FRESH TUMOR TISSUE CULTURES IN THE PEDIATRIC PRECISION ONCOLOGY PROGRAM INFORM

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Neuro-Oncology 2023年第SUPPLEMENT_1期25卷 i74–i75页

作者： Heike Peterziel Nora Jamaladdin Dina ElHarouni Xenia F Gerloff Sonja Herter Petra Fiesel Yannick Berker Mirjam Blattner-Johnson Kathrin Schramm Barbara C Jones David Reuss Laura Turunen Aileen Friedenauer Tim Holland-Letz Martin Sill Lena Weiser Christopher Previti Gnanaprakash Balasubramanian Nicolas U Gerber Johannes Gojo Caroline Hutter Ingrid Øra Olli Lohi Antonis Kattamis Bram de Wilde Frank Westermann Stephan Tippelt Norbert Graf Michaela Nathrath Monika Sparber-Sauer Astrid Sehested Christof M Kramm Uta Dirksen Olli Kallioniemi Stefan M Pfister Cornelis M van Tilburg David T W Jones Jani Saarela Vilja Pietiäinen Natalie Jäger Matthias Schlesner Annette Kopp-Schneider Sina Oppermann Till Milde Olaf Witt Ina Oehme Hopp Children’s Cancer Center Heidelberg (KiTZ) Heidelberg Germany Clinical Cooperation Unit Pediatric Oncology German Cancer Research Center (DKFZ) National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Consortium (DKTK) Heidelberg Germany Bioinformatics and Omics Data Analytics German Cancer Research Center (DKFZ) Division of Pediatric Neurooncology German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) Heidelberg Germany Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ) Heidelberg Germany Division of Pediatric Glioma Research German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) Heidelberg Germany Division of Pediatric Glioma Research German Cancer Research Center (DKFZ) Department of Pediatric Oncology Hematology Immunology and Pulmonology Heidelberg University Hospital and German Cancer Consortium (DKTK) Heidelberg Germany Department Neuropathology at Institute of Pathology Heidelberg University Hospital Heidelberg Germany Institute for Molecular Medicine Finland (FIMM) Helsinki Institute of Life Science (HiLIFE) University of Helsinki Helsinki Finland Division of Biostatistics German Cancer Research Center (DKFZ) Heidelberg Heidelberg Germany Division of Pediatric Neurooncology German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) Heidelberg Germany Core Facility Omics IT and Data Management (ODCF) German Cancer Research Center (DKFZ) Heidelberg Germany Department of Oncology University Children’s Hospital Zürich Zürich Switzerland Department of Pediatrics and Adolescent Medicine Comprehensive Cancer Center and Comprehensive Center for Pediatrics Medical University of Vienna Vienna Austria St. Anna Children’s Hospital Department of Pediatrics and Adolescent Medicine Medical University of Vienna and St. Anna Children’s Cancer Research Institute (CCRI) Vienna Austria Children’s Hospital Pediatric Oncology Skåne University Hospital Lund &amp Karolinska Univ

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.

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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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Gene expression imputation across multiple brain regions provides insights into schizophrenia risk (vol 51, pg 659, 2019)

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NATURE GENETICS 2019年第6期51卷 1068-1068页

作者： Huckins, Laura M. Dobbyn, Amanda Ruderfer, Douglas M. Hoffman, Gabriel Wang, Weiqing Pardinas, Antonio F. Rajagopal, Veera M. Als, Thomas D. Nguyen, Hoang T. Girdhar, Kiran Boocock, James Roussos, Panos Fromer, Menachem Kramer, Robin Domenici, Enrico Gamazon, Eric R. Purcell, Shaun Demontis, Ditte Borglum, Anders D. Walters, James T. R. O'Donovan, Michael C. Sullivan, Patrick Owen, Michael J. Devlin, Bernie Sieberts, Solveig K. Cox, Nancy J. Im, Hae Kyung Sklar, Pamela Stahl, Eli A. Pamela Sklar Division of Psychiatric Genomics Icahn School of Medicine at Mount Sinai New York NY USA Department of Genetics and Genomics Icahn School of Medicine at Mount Sinai New York NY USA Department of Psychiatry Icahn School of Medicine at Mount Sinai New York NY USA Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai New York NY USA Vanderbilt University Medical Center Nashville TN USA MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University Cardiff UK Department of Biomedicine Aarhus University Aarhus Denmark The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH Denmark Center for Integrative Sequencing Aarhus University Aarhus Denmark Department of Human Genetics David Geffen School of Medicine University of California Los Angeles Los Angeles CA USA Human Brain Collection Core National Institute of Mental Health Bethesda MD USA Laboratory of Neurogenomic Biomarkers Centre for Integrative Biology (CIBIO) University of Trento Trento Italy Clare Hall University of Cambridge Cambridge UK University of North Carolina at Chapel Hill Chapel Hill NC USA Karolinska Institutet Stockholm Sweden Department of Psychiatry University of Pittsburgh Pittsburgh PA USA Systems Biology Sage Bionetworks Seattle WA USA Section of Genetic Medicine Department of Medicine University of Chicago Chicago IL USA Integrated Technology Research Laboratories Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Japan Neuropsychiatry Section Department of Psychiatry Perelman School of Medicine University of Pennsylvania Philadelphia PA USA Neuropsychiatric Signaling Program Department of Psychiatry Perelman School of Medicine University of Pennsylvania Philadelphia PA USA Psychiatry JJ Peters Virginia Medical Center Bronx NY USA Department of Neuroscience Icahn School of Medicine at Mount Sinai New York New York NY USA Friedman Brain Institute

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

关键词： Gene expression Genome-wide association studies Schizophrenia Transcriptomics

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Genome-wide association study of long COVID

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Nature Genetics 2025年 1-16页

作者： Vilma Lammi Tomoko Nakanishi Samuel E. Jones Juha Karjalainen Martin Broberg Hele H. Haapaniemi Matti Pirinen Mari E. K. Niemi Mattia Cordioli Mark J. Daly Andrea Ganna Hanna M. Ollila J. Brent Richards Yukinori Okada Shea J. Andrews Beatriz Cortés Rafael de Cid Susana Iraola-Guzmán Natalia Blay Xavier Farré Heath E. O’Brien Thompson Hannah Patrick J. Short Ana Ochoa-Guzman Michelle Duran-Gomez Brian E. Fulton-Howard Masahiro Kanai Axel Schmidt Daniella Balla Julia Heggemann Sonja Schultz Pari Behzad Markus M. Nöthen Abigail Miller Kerstin U. Ludwig Ruth E. Mitchell George Davey Smith Nicholas J. Timpson Abdou Mousas Evangelos Evangelou Evangelia Ntzani Konstantinos K. Tsilidis Massimo Mangino Alicia Huerta-Chagoya Nasa Sinnott-Armstrong Elizabeth T. Cirulli Francisco Tanudjaja Efren Sandoval Nicole L. Washington Simon White Alexandre Bolze Kelly M. Schiabor Barrett Marc Vaudel Alex S. F. Kwong Amit K. Maiti Minttu M. Marttila Daniel C. Posner Alexis A. Rodriguez Chiara Batini Beatriz Guillen-Guio Olivia C. Leavy Anna L. Guyatt Catherine John Louise V. Wain Francesca Minnai Anna R. Dearman Benedict Hignell Meena Kumari C. A. Robert Warmerdam Lude H. Franke Celia B. Sequeros Søren Brunak David Westergaard Karina Banasik Thomas W. Winkler Iris M. Heid Daniel M. Jordan Ryan C. Thompson Alexander W. Charney Laura G. Sloofman Nicole W. Simons Noam D. Beckmann Raimonds Rešcenko Vita Rovite Peculis Raitis Monta Briviba Janis Klovinš Laura Ansone Lorenzo Miano Flora Peyvandi Francesco Malvestiti Nicola Montano Alessandra Bandera Francesco Bruno Arturo Blasi Jacqueline M. Lane Jakob M. Cherry Ryan K. Chung Laura Carvajal-Silva Kevin Aguilar-Valdés Leslie C. Cerpa Tamara V. Arévalo Eduardo Lamoza Alicia Colombo Ricardo A. Verdugo Erika Frangione Xu Xinyi Jennifer Taher Jordan Lerner-Ellis Lindsay Guare Shefali S. Verma Ekaterina Vergasova Michil Trofimov Layal Shaheen Nikolay Plotnikov Anna Kim Dmitrii Kharitonov Alexei Kamelin Alexander Rakitko Eirini Marouli Pasquale Striano Ummu Afeera Zainulabid Ashutosh Kumar Hajar Fa Institute for Molecular Medicine Finland (FIMM) Helsinki Institute of Life Science (HiLIFE) University of Helsinki Helsinki Finland Department of Human Genetics McGill University Montreal Quebec Canada Centre for Clinical Epidemiology Department of Medicine Lady Davis Institute Jewish General Hospital McGill University Montreal Quebec Canada Kyoto-McGill International Collaborative Program in Genomic Medicine Graduate School of Medicine Kyoto University Kyoto Japan Department of Genome Informatics Graduate School of Medicine the University of Tokyo Tokyo Japan Research Fellow Japan Society for the Promotion of Science Tokyo Japan Program in Medical and Population Genetics Broad Institute of Harvard and MIT Cambridge MA USA Stanley Center for Psychiatric Research Broad Institute of Harvard and MIT Cambridge MA USA Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA USA Department of Mathematics and Statistics University of Helsinki Helsinki Finland Department of Public Health University of Helsinki Helsinki Finland Broad Institute Cambridge MA USA Analytical and Translational Genetics Unit Massachusetts General Hospital Harvard Medical School Boston MA USA Center for Genomic Medicine Massachusetts General Hospital Boston MA USA Anesthesia Critical Care and Pain Medicine Massachusetts General Hospital and Harvard Medical School Boston MA USA Broad Institute of MIT and Harvard Cambridge MA USA Department of Twin Research King’s College London London UK 5 Prime Sciences Inc Montreal Quebec Canada Department of Epidemiology Biostatistics and Occupational Health McGill University Montreal Quebec Canada Department of Statistical Genetics Osaka University Graduate School of Medicine Suita Japan Laboratory for Systems Genetics RIKEN Center for Integrative Medical Sciences Yokohama Japan Laboratory of Statistical Immunology Immunology Frontier Research Center (WPI-IFReC) Osaka University Suita Japan Departmen

Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association ofFOXP4with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4’s role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

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Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

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Nature genetics 2019年第7期51卷 1192-1193页

作者： Rainer Malik Ganesh Chauhan Matthew Traylor Muralidharan Sargurupremraj Yukinori Okada Aniket Mishra Loes Rutten-Jacobs Anne-Katrin Giese Sander W van der Laan Solveig Gretarsdottir Christopher D Anderson Michael Chong Hieab H H Adams Tetsuro Ago Peter Almgren Philippe Amouyel Hakan Ay Traci M Bartz Oscar R Benavente Steve Bevan Giorgio B Boncoraglio Robert D Brown Adam S Butterworth Caty Carrera Cara L Carty Daniel I Chasman Wei-Min Chen John W Cole Adolfo Correa Ioana Cotlarciuc Carlos Cruchaga John Danesh Paul I W de Bakker Anita L DeStefano Marcel den Hoed Qing Duan Stefan T Engelter Guido J Falcone Rebecca F Gottesman Raji P Grewal Vilmundur Gudnason Stefan Gustafsson Jeffrey Haessler Tamara B Harris Ahamad Hassan Aki S Havulinna Susan R Heckbert Elizabeth G Holliday George Howard Fang-Chi Hsu Hyacinth I Hyacinth M Arfan Ikram Erik Ingelsson Marguerite R Irvin Xueqiu Jian Jordi Jiménez-Conde Julie A Johnson J Wouter Jukema Masahiro Kanai Keith L Keene Brett M Kissela Dawn O Kleindorfer Charles Kooperberg Michiaki Kubo Leslie A Lange Carl D Langefeld Claudia Langenberg Lenore J Launer Jin-Moo Lee Robin Lemmens Didier Leys Cathryn M Lewis Wei-Yu Lin Arne G Lindgren Erik Lorentzen Patrik K Magnusson Jane Maguire Ani Manichaikul Patrick F McArdle James F Meschia Braxton D Mitchell Thomas H Mosley Michael A Nalls Toshiharu Ninomiya Martin J O'Donnell Bruce M Psaty Sara L Pulit Kristiina Rannikmäe Alexander P Reiner Kathryn M Rexrode Kenneth Rice Stephen S Rich Paul M Ridker Natalia S Rost Peter M Rothwell Jerome I Rotter Tatjana Rundek Ralph L Sacco Saori Sakaue Michele M Sale Veikko Salomaa Bishwa R Sapkota Reinhold Schmidt Carsten O Schmidt Ulf Schminke Pankaj Sharma Agnieszka Slowik Cathie L M Sudlow Christian Tanislav Turgut Tatlisumak Kent D Taylor Vincent N S Thijs Gudmar Thorleifsson Unnur Thorsteinsdottir Steffen Tiedt Stella Trompet Christophe Tzourio Cornelia M van Duijn Matthew Walters Nicholas J Wareham Sylvia Wassertheil-Smoller James G Wilson Kerri L Wiggins Qiong Yang Salim Yusuf Joshua C Bis Tomi Institute for Stroke and Dementia Research (ISD) University Hospital LMU Munich Munich Germany. Centre for Brain Research Indian Institute of Science Bangalore India. INSERM U1219 Bordeaux Population Health Research Center University of Bordeaux Bordeaux France. Stroke Research Group Division of Clinical Neurosciences University of Cambridge Cambridge UK. Department of Neurology Institute for Neurodegenerative Disease Bordeaux University Hospital Bordeaux France. Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Yokohama Japan. Department of Statistical Genetics Osaka University Graduate School of Medicine Osaka Japan. Laboratory of Statistical Immunology Immunology Frontier Research Center (WPI-IFReC) Osaka University Suita Japan. Department of Neurology Massachusetts General Hospital (MGH) Harvard Medical School Boston MA USA. Laboratory of Experimental Cardiology Department of Cardiology Division of Heart and Lungs University Medical Center Utrecht University of Utrecht Utrecht the Netherlands. deCODE genetics/AMGEN Inc. Reykjavik Iceland. Center for Genomic Medicine MGH Boston MA USA. J. Philip Kistler Stroke Research Center Department of Neurology MGH Boston MA USA. Program in Medical and Population Genetics Broad Institute Cambridge MA USA. Population Health Research Institute McMaster University Hamilton Ontario Canada. Department of Epidemiology Erasmus University Medical Center Rotterdam the Netherlands. Department of Radiology and Nuclear Medicine Erasmus University Medical Center Rotterdam the Netherlands. Department of Medicine and Clinical Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan. Department of Clinical Sciences Lund University Malmö Sweden. INSERM Institut Pasteur de Lille LabEx DISTALZ-UMR1167 Risk Factors and Molecular Determinants of Aging-Related Diseases Université Lille Lille France. Centre Hospitalier Université Lille Epidemiology and Public Health D

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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