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Data integration of bulk and single-cell transcriptomics from cerebral organoids and post-mortem brains to identify cell types and cell type specific driver genes in autism

Research Square

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Research Square 2020年

作者： Lim, Elaine T. Chan, Yingleong Burns, Mannix J. Guo, Xiaoge Erdin, Serkan Tai, Derek J.C. Reichert, Julia M. Chan, Ying Kai Chiang, Jessica J. Meyers, Katharina Zhang, Xiaochang Walsh, Christopher A. Yankner, Bruce A. Raychaudhuri, Soumya Hirschhorn, Joel N. Gusella, James F. Talkowski, Michael E. Church, George M. DZNE Germany Program in Bioinformatics and Integrative Biology Departments of Neurology and Molecular Cell and Cancer Biology University of Massachusetts Medical School WorcesterMA01605 United States Department of Genetics Harvard Medical School BostonMA02115 United States Wyss Institute for Biologically Inspired Engineering Harvard University BostonMA02115 United States Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard CambridgeMA02115 United States Center for Genomic Medicine Massachusetts General Hospital BostonMA02115 United States Department of Neurology Massachusetts General Hospital BostonMA02115 United States Department of Human Genetics The Grossman Institute for Neuroscience Quantitative Biology and Human Behavior The University of Chicago ChicagoIL60637 United States Division of Genetics and Genomics Manton Center for Orphan Disease Research Howard Hughes Medical Institute Boston Children’s Hospital BostonMA02115 United States Departments of Pediatrics and Neurology Harvard Medical School BostonMA02115 United States Divisions of Genetics and Rheumatology Brigham and Women's Hospital Harvard Medical School BostonMA02115 United States Partners Center for Personalized Genetic Medicine BostonMA02115 United States Faculty of Medical and Human Sciences University of Manchester ManchesterM13 9PL United Kingdom Division of Endocrinology Boston Children's Hospital BostonMA02115 United States Center for Basic and Translational Obesity Research Boston Children's Hospital BostonMA02115 United States

Human-derived cerebral organoids demonstrate great promise for identifying cell types and cell type specific molecular processes perturbed by genetic variants associated with neuropsychiatric and neurodevelopmental disorders, which are notoriously challenging to study using animal models. However, considerable challenges remain in achieving robust, scalable and generalizable phenotyping of organoids to discover cell types and cell type specific genes. We perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data from human post-mortem brains and cerebral organoids, for the identification of cell types and cell type specific individual genes. We apply Orgo-Seq for two autism-associated loci: 16p11.2 deletions and 15q11-13 duplications, and identify neuroepithelial cells as critical cell types for 16p11.2 deletions, and discover novel and previously reported cell type specific driver genes. Finally, we validated our results that mutations in the KCTD13 gene in the 16p11.2 locus lead to imbalances in the proportion of neuroepithelial cells, using CRISPR/Cas9-edited mosaic organoids. Our work presents a quantitative technological framework to integrate multiple transcriptomics datasets to identify cell types and cell type specific driver genes associated with complex diseases using cerebral organoids. © 2020, CC BY.

关键词： Genes

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High-depth African genomes inform human migration and health (vol 586, pg 741, 2020)

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NATURE 2021年第7856期592卷 E26-E26页

作者： Choudhury, Ananyo Aron, Shaun Botigue, Laura R. Sengupta, Dhriti Botha, Gerrit Bensellak, Taoufik Wells, Gordon Kumuthini, Judit Shriner, Daniel Fakim, Yasmina J. Ghoorah, Anisah W. Dareng, Eileen Odia, Trust Falola, Oluwadamilare Adebiyi, Ezekiel Hazelhurst, Scott Mazandu, Gaston Nyangiri, Oscar A. Mbiyavanga, Mamana Benkahla, Alia Kassim, Samar K. Mulder, Nicola Adebamowo, Sally N. Chimusa, Emile R. Muzny, Donna Metcalf, Ginger Gibbs, Richard A. Matovu, Enock Bucheton, Bruno Hertz-Fowler, Christiane Koffi, Mathurin Macleod, Annette Mumba-Ngoyi, Dieudonne Noyes, Harry Nyangiri, Oscar A. Simo, Gustave Simuunza, Martin Rotimi, Charles Ramsay, Michele Choudhury, Ananyo Choudhury, Ananyo Aron, Shaun Botigue, Laura Sengupta, Dhriti Botha, Gerrit Bensellak, Taoufik Wells, Gordon Kumuthini, Judit Shriner, Daniel Fakim, Yasmina J. Ghoorah, Anisah W. Dareng, Eileen Odia, Trust Falola, Oluwadamilare Adebiyi, Ezekiel Hazelhurst, Scott Mazandu, Gaston Nyangiri, Oscar A. Mbiyavanga, Mamana Benkahla, Alia Kassim, Samar K. Mulder, Nicola Adebamowo, Sally N. Chimusa, Emile R. Rotimi, Charles Ramsay, Michele Adeyemo, Adebowale A. Lombard, Zane Hanchard, Neil A. Adebamowo, Clement Agongo, Godfred Boua, Romuald P. Oduro, Abraham Sorgho, Hermann Landoure, Guida Cisse, Lassana Diarra, Salimata Samassekou, Oumar Anabwani, Gabriel Matshaba, Mogomotsi Joloba, Moses Kekitiinwa, Adeodata Mardon, Graeme Mpoloka, Sununguko W. Kyobe, Samuel Mlotshwa, Busisiwe Mwesigwa, Savannah Retshabile, Gaone Williams, Lesedi Wonkam, Ambroise Moussa, Ahmed Adu, Dwomoa Ojo, Akinlolu Burke, David Salako, Babatunde O. Matovu, Enock Bucheton, Bruno Hertz-Fowler, Christiane Koffi, Mathurin Macleod, Annette Mumba-Ngoyi, Dieudonne Noyes, Harry Nyangiri, Oscar A. Simo, Gustave Simuunza, Martin Awadalla, Philip Bruat, Vanessa Gbeha, Elias Adeyemo, Adebowale A. Lombard, Zane Hanchard, Neil A. Sydney Brenner Institute for Molecular Bioscience Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa School of Electrical and Information Engineering University of the Witwatersrand Johannesburg South Africa Division of Human Genetics National Health Laboratory Service and School of Pathology Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa Navrongo Health Research Centre Navrongo Ghana Clinical Research Unit of Nanoro Institut de Recherche en Sciences de la Sante Bobo-Dioulasso Burkina Faso Center for Research in Agricultural Genomics (CRAG) Plant and Animal Genomics Program CSIC-IRTA-UAB-UB Barcelona Spain Computational Biology Division and H3ABioNet Department of Integrative Biomedical Sciences IDM University of Cape Town Cape Town South Africa System and Data Engineering Team Abdelmalek Essaadi University ENSA Tangier Morocco Centre for Proteomic and Genomic Research (CPGR) Cape Town South Africa South African National Bioinformatics Institute University of the Western Cape Bellville South Africa Africa Health Research Institute Durban South Africa Center for Research on Genomics and Global Health National Human Genome Research Institute National Institutes of Health Bethesda MD USA Department of Agriculture and Food Science Faculty of Agriculture University of Mauritius Reduit Mauritius Department of Digital Technologies Faculty of Information Communication & Digital Technologies University of Mauritius Reduit Mauritius Department of Public Health and Primary Care University of Cambridge Cambridge UK Institute of Human Virology Nigeria Abuja Nigeria Department of Epidemiology and Public Health University of Maryland School of Medicine University of Maryland Baltimore Baltimore MD USA University of Maryland Greenebaum Comprehensive Cancer Center University of Maryland School of Medicine University of Maryland Baltimore Baltimore MD USA Institute of Human Virology and Greeneba

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Author Correction: Perspectives on ENCODE

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Nature 2022年第7909期605卷 E4页

作者： Michael P Snyder Thomas R Gingeras Jill E Moore Zhiping Weng Mark B Gerstein Bing Ren Ross C Hardison John A Stamatoyannopoulos Brenton R Graveley Elise A Feingold Michael J Pazin Michael Pagan Daniel A Gilchrist Benjamin C Hitz J Michael Cherry Bradley E Bernstein Eric M Mendenhall Daniel R Zerbino Adam Frankish Paul Flicek Richard M Myers Department of Genetics School of Medicine Stanford University Palo Alto CA USA. mpsnyder@stanford.edu. Cardiovascular Institute Stanford School of Medicine Stanford CA USA. mpsnyder@stanford.edu. Functional Genomics Cold Spring Harbor Laboratory Cold Spring Harbor NY USA. University of Massachusetts Medical School Program in Bioinformatics and Integrative Biology Worcester MA USA. Department of Thoracic Surgery Clinical Translational Research Center Shanghai Pulmonary Hospital The School of Life Sciences and Technology Tongji University Shanghai China. Bioinformatics Program Boston University Boston MA USA. Yale University New Haven CT USA. Ludwig Institute for Cancer Research University of California San Diego La Jolla CA USA. Center for Epigenomics University of California San Diego La Jolla CA USA. Department of Biochemistry and Molecular Biology The Pennsylvania State University University Park PA USA. Altius Institute for Biomedical Sciences Seattle WA USA. Department of Genome Sciences University of Washington Seattle WA USA. Department of Medicine University of Washington Seattle WA USA. Department of Genetics and Genome Sciences Institute for Systems Genomics UConn Health Farmington CT USA. National Human Genome Research Institute National Institutes of Health Bethesda MD USA. Department of Genetics School of Medicine Stanford University Palo Alto CA USA. Broad Institute and Department of Pathology Massachusetts General Hospital and Harvard Medical School Boston MA USA. Biological Sciences University of Alabama in Huntsville Huntsville AL USA. HudsonAlpha Institute for Biotechnology Huntsville AL USA. European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Cambridge UK.

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World Congress integrative Medicine & Health 2017: Part one: Berlin, Germany. 3-5 May 2017

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BMC Complement Altern Med 2017年第SUPPL 1期17卷 322-322页

作者： Benno Brinkhaus Torkel Falkenberg Aviad Haramati Stefan N. Willich Josephine P. Briggs Merlin Willcox Klaus Linde Töres Theorell Lisa M. Wong Jeffrey Dusek Darong Wu David Eisenberg Bettina Berger Kathi Kemper Beate Stock-Schröer Hedda Sützl-Klein Rosaria Ferreri Gary Kaplan Harald Matthes Gabriele Rotter Elad Schiff Zahi Arnon Eckhard Hahn Christina M. Luberto David Martin Silke Schwarz Diethard Tauschel Andrew Flower Harsha Gramminger Hedwig H. Gupta S. N. Gupta Annette Kerckhoff Christian S. Kessler Andreas Michalsen Eun S. Kim Eun H. Jang Rana Kim Sae B. Jan Martin Mittwede Wiebke Mohme Eran Ben-Arye Massimo Bonucci Bashar Saad Thomas Breitkreuz Elio Rossi Rejin Kebudi Michel Daher Samaher Razaq Nahla Gafer Omar Nimri Mohamed Hablas Gunver Sophia Kienle Noah Samuels Michael Silbermann Lena Bandelin Anna-Lena Lang Eva Wartner Christoph Holtermann Maxwell Binstock Robert Riebau Edin Mujkanovic Holger Cramer Romy Lauche Andres Michalsen Lesley Ward Dominik Irnich Wolfram Stör Geoffrey Burnstock Hans-Georg Schaible Thomas Ots Jost Langhorst Tobias Sundberg Catherina Amarell Melanie Anheyer Marion Eckert Mercedes Ogal Annette Schönauer Birgit Reisenberger Bernhard Brand Dennis Anheyer Gustav Dobos Matthias Kroez Aldo Ammendola Jun J. Mao Claudia Witt Yufei Yang Miriam Oritz Markus Horneber Petra Voiß Alexandra von Rosenstiel Catharina Amarell Friedemann Schad Marc Schläppi Matthias Kröz Arndt Büssing Gil Bar-Sela David Avshalomov Samuel Attias Sian Cotton Miek Jong Mats Jong Christian Scheffer Friedrich Edelhäuser Abdullah AlBedah Myeong Soo Lee Mohamed Khalil Keiko Ogawa Yoshiharu Motoo Junsuke Arimitsu Masao Ogawa Genki Shimizu Rainer Stange Karin Kraft Kenny Kuchta Kenji Watanabe D Bonin Harald Gruber Sabine Koch Urs Pohlmann Christine Caldwell Barbara Krantz Ria Kortum Lily Martin Lisa S. Wieland Ben Kligler Susan Gould-Fogerite Yuqing Zhang John J. Riva Michael Lumpkin Emily Ratner Liu Ping Pei Jian Gesa-Meyer Hamme Xiaosong Mao Han Chouping Sven Schröder Josef Hummelsberger Michael Wullinger Marc Brodzky Chr Institute for Social Medicine Epidemiology and Health Economics Charité – Universitätsmedizin Berlin Berlin Germany Department of Neurobiology Care Sciences and Society Division of Nursing Research Group Integrative Care Karolinska Institutet Stockholm Sweden I C – The Integrative Care Science Center Järna Sweden Department of Biochemistry Molecular and Cellular Biology Georgetown University Medical Center Washington DC USA Department of Medicine Georgetown University Medical Center Washington DC USA NCCIH NIH Bethesda MD USA Department of Primary Care and Population Sciences University of Southampton Aldermoor Health Centre Coxford Rd Southampton 2016 5ST UK Institute of General Practice Technical University Munich Munich Germany Department of Neuroscience Karolinska Institute Stockholm Sweden Stress Research Institute Stockholm University Stockholm Sweden Arts and Humanities Initiative Harvard Medical School Boston MA 02115 USA Psychosomatic medicine Neuropsychology Allina Health Minneapolis MN USA nd Affiliated Hospital of Guangzhou University of Chinese Medicine Guangzhou China Department of Nutrition Harvard University T H Chan School of Public Health Boston MA 02115 USA Department of Health University of Witten/Herdecke Witten/Herdecke Germany OSU Blacklick OH USA Carstens-Foundation and FORUM D-45276 Essen Germany ESIHR (European Society for Integrative Health Care) A-1070 Vienna Austria Hospital Centre of Integrated Medicine Hospital of Pitiglian o ASL SudEst Toscana Grosseto Italy The Kaplan Center for Integrative Medicine Georgetown University McLean VA USA Hospital Havelhöhe Berlin Germany Institute for Social Medicine Epidemiology and Health Economics Charité University Hospital Berlin Germany Internal medicine and Complementary medicine service Bnai Zion Medical Center Haifa Israel Complementary-Integrative Surgery Service Bnai Zion Medical Center Haifa Israel The Emek Yezreel Academic College Yezreel Valley Israel Medicine

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Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors (vol 19, pg 302, 2018)

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NATURE IMMUNOLOGY 2018年第6期19卷 645-645页

作者： Patin, Etienne Hasan, Milena Bergstedt, Jacob Rouilly, Vincent Libri, Valentina Urrutia, Alejandra Alanio, Cecile Scepanovic, Petar Hammer, Christian Joensson, Friederike Beitz, Benoit Quach, Helene Lim, Yoong Wearn Hunkapiller, Julie Zepeda, Magge Green, Cherie Piasecka, Barbara Leloup, Claire Rogge, Lars Huetz, Francois Peguillet, Isabelle Lantz, Olivier Fontes, Magnus Di Santo, James P. Thomas, Stephanie Fellay, Jacques Duffy, Darragh Quintana-Murci, Lluis Albert, Matthew L. Unit of Human Evolutionary Genetics Department of Genomes & Genetics Institut Pasteur Paris France CNRS UMR 2000 Paris France Center of Bioinformatics Biostatistics and Integrative Biology Institut Pasteur Paris France Center for Translation Research Institut Pasteur Paris France Department of Automatic Control Lund University Lund Sweden International Group for Data Analysis Institut Pasteur Paris France Laboratory of Dendritic Cell Immunobiology Department of Immunology Institut Pasteur Paris France INSERM U1223 Paris France Department of Cancer Immunology Genentech South San Francisco CA USA School of Life Sciences École Polytechnique Fédérale de Lausanne Lausanne Switzerland Swiss Institute of Bioinformatics Lausanne Switzerland Antibodies in Therapy and Pathology Department of Immunology Institut Pasteur Paris France INSERM U760 Paris France Department of Human Genetics Genentech South San Francisco CA USA Employee Donation Program Genentech South San Francisco CA USA Department of Development Sciences Genentech South San Francisco CA USA Immunoregulation Unit Department of Immunology Institut Pasteur Paris France INSERM U783 Faculté de Médecine Site Necker-Enfants Malades Université Paris Descartes Paris France Lymphocyte Population Biology CNRS URA 1961 Institut Pasteur Paris France Center of Clinical Investigations CIC-BT1428 IGR/Curie Paris France Department of Biopathology Institut Curie Paris France Equipe Labellisée de la Ligue de Lutte Contre le Cancer Institut Curie Paris France INSERM/Institut Curie U932 Paris France Centre for Mathematical Sciences Lund University Lund Sweden Innate Immunity Unit Institut Pasteur Paris France St. Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch Rockefeller University New York NY USA Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children Paris France Paris Descartes University Imagine Insti

The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.

关键词： Activated Lymphocyte Genetic factors Immunity Nonspecific Immune Cell Variation

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GREGoR: Accelerating genomics for Rare Diseases

arXiv

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arXiv 2024年

作者： Dawood, Moez Heavner, Ben Wheeler, Marsha M. Ungar, Rachel A. LoTempio, Jonathan Wiel, Laurens Berger, Seth Bernstein, Jonathan A. Chong, Jessica X. Délot, Emmanuèle C. Eichler, Evan E. Gibbs, Richard A. Lupski, James R. Shojaie, Ali Talkowski, Michael E. Wagner, Alex H. Wei, Chia-Lin Wellington, Christopher Wheeler, Matthew T. Carvalho, Claudia M.B. Gifford, Casey A. May, Susanne Miller, Danny E. Rehm, Heidi L. Sedlazeck, Fritz J. Vilain, Eric O'Donnell-Luria, Anne Posey, Jennifer E. Chadwick, Lisa H. Bamshad, Michael J. Montgomery, Stephen B. Human Genome Sequencing Center Baylor College of Medicine HoustonTX United States Department of Molecular and Human Genetics Baylor College of Medicine HoustonTX United States Medical Scientist Training Program Baylor College of Medicine HoustonTX United States Department of Biostatistics University of Washington SeattleWA United States Department of Genetics School of Medicine Stanford University StanfordCA United States Department of Pathology School of Medicine Stanford University Stanford CA United States Stanford Center for Biomedical Ethics School of Medicine Stanford University Stanford CA United States Institute for Clinical and Translational Science University of California IrvineCA United States Division of Cardiovascular Medicine School of Medicine Stanford University Stanford CA United States Division of Genetics and Metabolism Children’s National Rare Disease Institute WashingtonDC United States Center for Genetic Medicine Research Children’s National Rare Disease Institute WashingtonDC United States Department of Genomics and Precision Medicine George Washington University WashingtonDC United States Department of Pediatrics School of Medicine Stanford University Stanford CA United States Department of Pediatrics Dvision of Genetic Medicine University of Washington SeattleWA United States Brotman Baty Institute for Precision Medicine University of Washington SeattleWA United States Department of Genome Sciences University of Washington SeattleWA United States Howard Hughes Medical Institute University of Washington SeattleWA United States Department of Pediatrics Baylor College of Medicine HoustonTX United States Center for Genomic Medicine Massachusetts General Hospital BostonMA United States Program in Medical and Population Genetics Broad Institute of MIT and Harvard BostonMA United States Department of Neurology Massachusetts General Hospital Harvard Medical School BostonMA United States Stanley Center for

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize, and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Further, all data generated, currently representing ~7500 individuals from ~3000 families, is rapidly made available to researchers worldwide via the Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) to catalyze global efforts to develop approaches for genetic diagnoses in rare diseases (https://***/data). The majority of these families have undergone prior clinical genetic testing but remained unsolved, with most being exome-negative. Here, we describe the collaborative research framework, datasets, and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics. © 2024, CC BY.

关键词： Genome

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An open science study of ageing in companion dogs (vol 602, g 51, 2022)

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NATURE 2022年第7924期608卷 E33-E33页

作者： Creevy, Kate E. Akey, Joshua M. Kaeberlein, Matt Promislow, Daniel E. L. Department of Small Animal Clinical Sciences Texas A&M University College of Veterinary Medicine & Biomedical Sciences College Station TX USA Lewis-Sigler Institute for Integrative Genomics Princeton University Princeton NJ USA Department of Laboratory Medicine and Pathology University of Washington School of Medicine Seattle WA USA Department of Biology University of Washington Seattle WA USA Institute for Stem Cell and Regenerative Medicine University of Washington Seattle WA USA Department of Clinical Microbiology and Immunology Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel Blavatnik School of Computer Science Tel Aviv University Tel Aviv Israel Santa Fe Institute Santa Fe NM USA Cornell Veterinary Biobank College of Veterinary Medicine Cornell University Ithaca NY USA Department of Sociology University of Washington Seattle WA USA Center for Studies in Demography and Ecology Seattle WA USA Department of Small Animal Medicine and Surgery University of Georgia College of Veterinary Medicine Athens GA USA Department of Veterinary Physiology and Pharmacology Texas A&M University College of Veterinary Medicine & Biomedical Sciences College Station TX USA Department of Family Medicine University of Washington Seattle WA USA Department of Epidemiology University of Washington Seattle WA USA Department of Global Health University of Washington Seattle WA USA Epidemiology Program Fred Hutchinson Cancer Research Center Seattle WA USA Department of Veterinary Pathobiology Texas A&M University College of Veterinary Medicine & Biomedical Sciences College Station TX USA Bioinformatics and Integrative Biology University of Massachusetts Chan Medical School Worcester MA USA Broad Institute of MIT and Harvard Cambridge MA USA Department of Biostatistics University of Washington Seattle WA USA Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA Department of Population Health Sciences Vir

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Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer (Dec, 10.1038/s41467-019-13824-9, 2022)

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NATURE COMMUNICATIONS 2022年第1期13卷 1-1页

作者： Sieverling, Lina Hong, Chen Koser, Sandra D. Ginsbach, Philip Kleinheinz, Kortine Hutter, Barbara Braun, Delia M. Cortes-Ciriano, Isidro Xi, Ruibin Kabbe, Rolf Park, Peter J. Eils, Roland Schlesner, Matthias Brors, Benedikt Rippe, Karsten Jones, David T. W. Feuerbach, Lars Division of Applied Bioinformatics German Cancer Research Center (DKFZ) 69120 Heidelberg Germany Faculty of Biosciences Heidelberg University 69120 Heidelberg Germany Division of Applied Bioinformatics German Cancer Research Center (DKFZ) Heidelberg Germany Faculty of Biosciences Heidelberg University Heidelberg Germany Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ) 69120 Heidelberg Germany Department for Bioinformatics and Functional Genomics Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant 69120 Heidelberg Germany Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ) Heidelberg Germany Institute of Pharmacy and Molecular Biotechnology and BioQuant Heidelberg University Heidelberg Germany German Cancer Consortium (DKTK) Heidelberg Germany National Center for Tumor Diseases (NCT) Heidelberg Heidelberg Germany Heidelberg Center for Personalized Oncology (DKFZ-HIPO) German Cancer Research Center (DKFZ) Heidelberg Germany German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ) Heidelberg Germany Division of Chromatin Networks German Cancer Research Center (DKFZ) and BioQuant 69120 Heidelberg Germany Department of Biomedical Informatics Harvard Medical School Boston Massachusetts 02115 USA Department of Chemistry Centre for Molecular Science Informatics University of Cambridge Cambridge CB2 1EW UK Ludwig Center at Harvard Medical School Boston Massachusetts 02115 USA Department of Biomedical Informatics Harvard Medical School Boston MA USA Department of Chemistry Centre for Molecular Science Informatics University of Cambridge Cambridge UK Ludwig Center at Harvard Medical School Boston MA USA School of Mathematical Sciences and Center for Statistical Science Peking University Beijing 100871 China Heidelberg University Heidelberg Germany New BIH Digital Health Center Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin Berlin Germany Bioi

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Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information (vol 91, pg 626, 2022)

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BIOLOGICAL PSYCHIATRY 2022年第7期91卷 690-690页

作者： Maihofer, Adam X. Vinkers, Christiaan H. Department of Psychiatry University of California San Diego La Jolla California Department of Family Medicine and Public Health University of California San Diego La Jolla California Center of Excellence for Stress and Mental Health Veterans Affairs Healthcare System San Diego California. Electronic address: amaihofer@health.ucsd.edu. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Department of Psychiatry Massachusetts General Hospital Boston Massachusetts. Social Genetic and Developmental Psychiatry Centre Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom National Institute of Health Research Maudsley Biomedical Research Centre King's College London London United Kingdom. Department of Psychiatry Harvard Medical School Boston Massachusetts Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts Center of Excellence in Depression and Anxiety Disorders Belmont Massachusetts. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts. Department of Psychiatry University of California San Diego La Jolla California Center of Excellence for Stress and Mental Health Veterans Affairs Healthcare System San Diego California Research Service Veterans Affairs Healthcare System San Diego California. Duke Molecular Physiology Institute Duke University School of Medicine Durham North Carolina. Department of Psychiatry Veterans Affairs Connecticut Healthcare System West Haven Connecticut Department of Psychiatry Yale University School of Medicine New Haven Connecticut. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Department of Epidemiology Columbia University Mailman School of Public Health New York. Division of Mental Health Atlanta Veterans Affairs Medical Center

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

关键词： GWAS Genetics Heritability PTSD PheWAS Trauma

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Publisher Correction: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

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Nature genetics 2022年第8期54卷 1259页

作者： Danny Antaki James Guevara Adam X Maihofer Marieke Klein Madhusudan Gujral Jakob Grove Caitlin E Carey Oanh Hong Maria J Arranz Amaia Hervas Christina Corsello Keith K Vaux Alysson R Muotri Lilia M Iakoucheva Eric Courchesne Karen Pierce Joseph G Gleeson Elise B Robinson Caroline M Nievergelt Jonathan Sebat Biomedical Sciences Graduate Program University of California San Diego La Jolla CA USA. Beyster Center for Psychiatric Genomics University of California San Diego La Jolla CA USA. Department of Psychiatry University of California San Diego La Jolla CA USA. Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA. Institute for Genomic Medicine University of California San Diego La Jolla CA USA. Department of Neurosciences University of California San Diego La Jolla CA USA. Department of Biomedicine Aarhus University Aarhus Denmark. The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH Aarhus Denmark. Center for Genomics and Personalized Medicine and Center for Integrative Sequencing iSEQ Aarhus Denmark. Bioinformatics Research Centre Aarhus University Aarhus Denmark. Harvard T.H. Chan School of Public Health Broad Institute of the Massachusetts Institute of Technology and Harvard Cambridge MA USA. Research Laboratory Unit Fundacio Docencia i Recerca Mutua Terrassa Spain. Child and Adolescent Mental Health Unit Hospital Universitari Mútua de Terrassa Barcelona Spain. TEACCH Autism Program University of North Carolina Chapel Hill NC USA. Human Longevity Inc. San Diego CA USA. Department of Pediatrics and Department of Cellular & Molecular Medicine University of California San Diego School of Medicine Center for Academic Research and Training in Anthropogeny Archealization Center Kavli Institute for Brain and Mind La Jolla CA USA. Autism Center of Excellence University of California San Diego La Jolla CA USA. Beyster Center for Psychiatric Genomics University of California San Diego La Jolla CA USA. jsebat@ucsd.edu. Department of Psychiatry University of California San Diego La Jolla CA USA. jsebat@ucsd.edu. Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA. jsebat@ucsd.edu. Institute for Genomic Medicine University of Californi

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