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Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)

EUROPEAN JOURNAL OF HUMAN GENETICS 2022年第5期30卷 630-631页

作者： Dareng, Eileen O. Tyrer, Jonathan P. Barnes, Daniel R. Jones, Michelle R. Yang, Xin Aben, Katja K. H. Adank, Muriel A. Agata, Simona Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Aravantinos, Gerasimos Arun, Banu K. Augustinsson, Annelie Balmana, Judith Bandera, Elisa V. Barkardottir, Rosa B. Barrowdale, Daniel Beckmann, Matthias W. Beeghly-Fadiel, Alicia Benitez, Javier Bermisheva, Marina Bernardini, Marcus Q. Bjorge, Line Black, Amanda Bogdanova, Natalia V. Bonanni, Bernardo Borg, Ake Brenton, James D. Budzilowska, Agnieszka Butzow, Ralf Buys, Saundra S. Cai, Hui Caligo, Maria A. Campbell, Ian Cannioto, Rikki Cassingham, Hayley Chang-Claude, Jenny Chanock, Stephen J. Chen, Kexin Chiew, Yoke-Eng Chung, Wendy K. Claes, Kathleen B. M. Colonna, Sarah Cook, Linda S. Couch, Fergus J. Daly, Mary B. Dao, Fanny Davies, Eleanor de la Hoya, Miguel de Putter, Robin Dennis, Joe DePersia, Allison Devilee, Peter Diez, Orland Ding, Yuan Chun Doherty, Jennifer A. Domchek, Susan M. Dork, Thilo du Bois, Andreas Durst, Matthias Eccles, Diana M. Eliassen, Heather A. Engel, Christoph Evans, Gareth D. Fasching, Peter A. Flanagan, James M. Fortner, Renee T. Machackova, Eva Friedman, Eitan Ganz, Patricia A. Garber, Judy Gensini, Francesca Giles, Graham G. Glendon, Gord Godwin, Andrew K. Goodman, Marc T. Greene, Mark H. Gronwald, Jacek Hahnen, Eric Haiman, Christopher A. Hakansson, Niclas Hamann, Ute Hansen, Thomas V. O. Harris, Holly R. Hartman, Mikael Heitz, Florian Hildebrandt, Michelle A. T. Hogdall, Estrid Hogdall, Claus K. Hopper, John L. Huang, Ruea-Yea Huff, Chad Hulick, Peter J. Huntsman, David G. Imyanitov, Evgeny N. Isaacs, Claudine Jakubowska, Anna James, Paul A. Janavicius, Ramunas Jensen, Allan Johannsson, Oskar Th. John, Esther M. Jones, Michael E. Kang, Daehee Karlan, Beth Y. Karnezis, Anthony Kelemen, Linda E. Khusnutdinova, Elza Kiemeney, Lambertus A. Kim, Byoung-Gie Kjaer, Susanne K. Komenaka, Ian Kupryjanczyk, Jolanta Kurian, Allison W. Kwong, Ava Lambrechts, Diether Larson, Melissa C. Lazaro, Conxi L University of Cambridge Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Cambridge UK University of Cambridge Centre for Cancer Genetic Epidemiology Department of Oncology Cambridge UK Center for Bioinformatics and Functional Genomics Cedars-Sinai Medical Center Los Angeles CA USA Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen The Netherlands Netherlands Comprehensive Cancer Organisation Utrecht The Netherlands The Netherlands Cancer Institute—Antoni van Leeuwenhoek hospital Family Cancer Clinic Amsterdam The Netherlands Veneto Institute of Oncology IOV—IRCCS Immunology and Molecular Oncology Unit Padua Italy Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital Fred A. Litwin Center for Cancer Genetics Toronto ON Canada University of Toronto Department of Molecular Genetics Toronto ON Canada University of California Irvine Department of Epidemiology Genetic Epidemiology Research Institute Irvine CA USA N.N. Alexandrov Research Institute of Oncology and Medical Radiology Minsk Belarus ‘Agii Anargiri’ Cancer Hospital Athens Greece University of Texas MD Anderson Cancer Center Department of Breast Medical Oncology Houston TX USA Lund University Department of Cancer Epidemiology Clinical Sciences Lund Sweden Vall d’Hebron Institute of Oncology Hereditary cancer Genetics Group Barcelona Spain University Hospital of Vall d’Hebron Department of Medical Oncology Barcelona Spain Rutgers Cancer Institute of New Jersey Cancer Prevention and Control Program New Brunswick NJ USA Landspitali University Hospital Department of Pathology Reykjavik Iceland University of Iceland BMC (Biomedical Centre) Faculty of Medicine Reykjavik Iceland University Hospital Erlangen Friedrich-Alexander-University Erlangen-Nuremberg Department of Gynecology and Obstetrics Comprehensive Cancer Center ER-EMN Erlangen Germany Vanderbilt University School of Medicine Division of Epidemiology Department

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

关键词： Clinical genetics Genetic markers Risk factors Biomedicine general Human Genetics bioinformatics Gene Expression Cytogenetics

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Building a Model for Predicting Target Gene Expression in Rice T-DNA Insertional Mutants by Machine Learning Approaches

Research Square

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Research Square 2020年

作者： Liao, Chi-Chou Chen, Liang-Jwu Lo, Shuen-Fang Chen, Chi-Wei Chen, Jia-Jyun Chu, Yen-Wei Institute of Molecular Biology National Chung Hsing University Taichung Taiwan Agricultural Biotechnology Center National Chung Hsing University Taichung Taiwan Institute of Molecular Biology Academia Sinica Taipei Taiwan Department of Computer Science and Engineering National Chung Hsing University Taichung Taiwan Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan Biotechnology Center National Chung Hsing University Taichung Taiwan Ph.D. Program in Translational Medicine National Chung Hsing University Taichung Taiwan Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung402 Taiwan

Background: T-DNA activation-tagging technology is widely used to enhance flanking gene expression near the site of insertion for functional genomics research in rice. However, whether the expression of a gene of interest is enhanced must be validated experimentally. Results: In this study, we built a model to predict gene expression in T-DNA mutants by machine learning approaches, thereby improving the efficiency of screening for activated genes. We gathered experimental consisting of gene expression data in T-DNA mutants and captured the PROMOTER and MIDDLE sequences for encoding. In first-layer models, SVM models were constructed with nine features consisting of information about biological function and local and global sequences. Feature-encoding based on the PROMOTER sequence was weighted by logistic regression. The second-layer models integrated 16 first-layer models with feature selection and the algorithm, which were selected from nine feature selection methods and 65 classified methods, respectively. The accuracy of the final two-layer machine learning model, referred to as was 99.3% based on fivefold cross-validation, and 85.6% based on independent-testing. Conclusion: We discovered that the information within the local sequence had a greater contribution than the global sequence with respect to classification had a good predictive ability for target genes within 20 from the 35S enhancer. Based on the analysis of significant sequences, the G-box regulatory sequence may also play an important role in the mechanism of activation of the 35S enhancer. © 2020, CC BY.

关键词： Gene expression

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BTEX exposure and its body burden pose differential risks for asthma and its phenotypic clusters

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Allergy 2023年第7期78卷 2036-2040页

作者： Yuan-Ting Hsu Chao-Chien Wu Chin-Chou Wang Wen-Yu Chung Chau-Chyun Sheu Yi-Hsin Yang Ming-Yen Cheng Ruay-Sheng Lai Sum-Yee Leung Chi-Cheng Lin Yu-Feng Wei Ching-Hsiung Lin Sheng-Hao Lin Jeng-Yuan Hsu Wei-Chang Huang Chia-Cheng Tseng Yung-Fa Lai Meng-Hsuan Cheng Huang-Chi Chen Chih-Jen Yang Chian-Heng Su Chien-Jen Wang Shih-Chang Hsu Chih-Hsing Hung Chon-Lin Lee Ming-Shyan Huang Shau-Ku Huang National Institute of Environmental Health Sciences National Health Research Institutes Miaoli Taiwan. Department of Internal Medicine Division of Pulmonary and Critical Care Medicine Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung Taiwan. Department of Public Health Kaohsiung Medical University Kaohsiung Taiwan. Department of Computer Science and Information Engineering National Kaohsiung University of Science and Technology Kaohsiung Taiwan. Department of Internal Medicine Division of Pulmonary and Critical Care Medicine Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan. Department of Internal Medicine School of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan. National Institute of Cancer Research National Health Research Institutes Tainan Taiwan. Department of Mathematics Hong Kong Baptist University Hong Kong China. Division of Chest Medicine Kaohsiung Veterans General Hospital Kaohsiung Taiwan. Department of Internal Medicine Chest Division Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital Pingtung Taiwan. Department of Internal Medicine E-Da Cancer Hospital I-Shou University Kaohsiung Taiwan. Department of Internal Medicine Division of Chest Medicine Changhua Christian Hospital Changhua Taiwan. Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan. Department of Recreation and Holistic Wellness MingDao University Changhua Taiwan. Department of Medical Research Division of Clinical Research Taichung Veterans General Hospital Taichung Taiwan. Department of Internal Medicine Division of Chest Medicine Taichung Veterans General Hospital Taichung Taiwan. Department of Medical Technology Jen-Teh Junior College of Medicine Nursing and Management Miaoli Taiwan. School of Medicine Chung Shan Medical University Taichung Taiwan. Ph.D. Program in Translational Medicine National Chung Hsing Universi

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Lineage relationship of CD8^＋ T cell subsets is revealed by progressive changes in the epigenetic landscape

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Cellular & Molecular Immunology 2016年第4期13卷 502-513页

作者： Joseph G. Crompton Manikandan Narayanan Suresh Cuddapah Rahul Roychoudhuri Yun Ji Wenjing Yang Shashank J. Patel Madhusudhanan Sukumar Douglas C. Palmer Weiqun Peng Ena Wang Francesco M. Marincola Christopher A. Klebanoff Keji Zhao John S. Tsang Luca Gatt-inoni Nicholas P. Restifo Surgery Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA Cambridge Institute for Medical Research University of Cam bridge Cambridge CB20XY UK Systems Genomics and Bioinformatics Unit Laboratory of Systems Biology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD 20892 USA Department of Environmental Medicine New York University School of Medicine Tuxedo NY 10987 USA Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA Department of Physics The George Washington University Washington DC 20052 USA Research Branch Sidra Medical and Research Centre Doha Qatar Infectious Disease and Immunogenetics Section Department of Transfusion Medicine Clinical Center National Institutes of Health Bethesda MD 20892 USA Clinical Investigator Development Program NCI/NIH Bethesda MD 20892 USA Systems Biology Center National Heart Lung and Blood Institute National Institutes of Health Bethesda MD 20892 USA. Lombardi Comprehensive Cancer Center Georgetown University Washington. DC 20007. United States. Bethesda. MD 20892. USA.

To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8＋ T cells. Using a ChlP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 （H3K4me3） and H3 lysine 27 （H3K27me3） trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8＋ T-cell subsets. Taken together, our results suggest that CD8＋ lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory.

关键词： T淋巴细胞干细胞基因表达记忆抗原 CD8 赖氨酸胰岛素组蛋白类

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从磷酸酯化学刍议各类磷酸酶和三磷酸核苷酶的生物化学转化与机制

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化学教育（中英文） 2023年第8期44卷 19-29页

作者：王志鹏蒋振雄 Maggie Chen 张璇马新雨车子良 Division of Genetics Department of MedicineBrigham and Women's HospitalDepartment of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBostonMA 02115USA Department of Chemistry Texas A&M UniversityCollege StationTX77840USA 清华大学化学系北京100084 Department of Biology Texas A&M UniversityCollege StationTX 77840USA Computational Biology and Bioinformatics Program Duke Center for Genomics and Computational BiologyDuke University School of MedicineDurhamNC 27705USA Department of Microbiology Miami UniversityOxfordOH 45056USA Department of Chemistry and Chemical Biology Harvard UniversityCambridgeMA02138US 清华大学生命学院北京100084 Department of Mathematics Harvard UniversityMA 02138 Citadel Securities LLC131 SouthDearborn St.Chicago Illinois 60603USA

磷作为一切生物体的必需元素,参与了包括生命体能量代谢、结构调控、遗传信息传递等在内的必要过程,其重要性不言而喻。然而,在国内基础学科教学过程中,基于酶促反应的调控机制和反应机理被拆分到众多生化专业相关的课程中,并未能得到... 详细信息

磷作为一切生物体的必需元素,参与了包括生命体能量代谢、结构调控、遗传信息传递等在内的必要过程,其重要性不言而喻。然而,在国内基础学科教学过程中,基于酶促反应的调控机制和反应机理被拆分到众多生化专业相关的课程中,并未能得到系统性的剖析与讲解。本文从基础磷酸酯和磷酸酐的化学结构及反应特性入手,分别讨论了生物体中磷酸酯相关的调控酶类,并对最重要的一类磷酸酐——三磷酸腺苷在生物体内的转化关系做了系统性的讲解及分析。作为对磷元素相关的生命化学过程的梳理归纳,希望对化学及生命科学的教学与科研实验设计有所助益。

关键词：磷化学磷酸酯酶促反应激酶三磷酸腺苷

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Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic value in SMYD2

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Cancer Treatment and Research Communications 2018年 15卷 21-31页

作者： Galván-Femenía, Iván Guindo, Marta Duran, Xavier Calabuig-Fariñas, Sílvia Mercader, Josep Maria Ramirez, Jose Luis Rosell, Rafael Torrents, David Carreras, Anna Kohno, Takashi Jantus-Lewintre, Eloisa Camps, Carlos Perucho, Manuel Sumoy, Lauro Yokota, Jun de Cid, Rafael Genomes For life-GCAT Lab. Program of Predictive and Personalized Medicine of Cancer (PMPPC) Institute for Health Science Research Germans Trias i Pujol (IGTP) Can Ruti Biomedical Campus Crta de Can Ruti Camí de les Escoles S/N Badalona 08916 Barcelona Spain Barcelona Supercomputing Center (BSC-CNS) Joint BSC-CRG-IRB Research Program in Computational Biology Carrer de Jordi Girona 29-31 Barcelona 08034 Spain Department of Medical Oncology Hospital General Universitario de Valencia Avenida Tres Cruces 2 València 46014 Spain Molecular Oncology Laboratory Fundación Hospital General Universitario de Valencia Avda. Tres Cruces s/n València 46014 Spain Department of Pathology Universitat de València Av. de Blasco Ibáñez 13 València 46010 Spain Program of Predictive and Personalized Medicine of Cancer (PMPPC) Institute for Health Science Research Germans Trias i Pujol (IGTP) Can Ruti Biomedical Campus Crta de Can Ruti Camí de les Escoles S/N Badalona 08916 Barcelona Spain ICREA Catalan Institution for Research and Advanced Studies Spain Division of Genome Biology National Cancer Center Research Institute 5-1-1 Tsukiji Chuo-ku Tokyo 104-0045 Japan Molecular Oncology Laboratory Fundación Hospital General Universitario de València Avda. Tres Cruces s/n València 46014 Spain Department of Biotechnology Universitat Politècnica de València Camí de Vera s/n València 46022 Spain Department of Medicine Universitat de València Av. de Blasco Ibáñez 13 València 46010 Spain Genomics and Bioinformatics. Program of Predictive and Personalized Medicine of Cancer (PMPPC) Institute for Health Science Research Germans Trias i Pujol (IGTP) Can Ruti Biomedical Campus Crta de Can Ruti Camí de les Escoles S/N Badalona 08916 Barcelona Spain Programs in Metabolism and Medical & Population Genetics Broad Institute of Harvard and MIT Cambridge Massachusetts United States Diabetes Unit and Center for Human Genetic Research Massachusetts General Hospital Boston Massachuse

Objective: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment. Materials and Methods: We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain). Results: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLC patients. Conclusion: Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLC patients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy. A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLC patients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in human carcinogenesis as well in resistance to chemotherapy. © 2018 The Authors

关键词： Advanced stage Genome-Wide-Association Studies Lung cancer NSCLC Prognostic factors

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Emergence of ceftazidime-avibactam resistance through in-vivo bla KPC-2 to bla KPC-33 conversion during treatment of ST11 Klebsiella pneumoniae associated infections

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International Journal of Antimicrobial Agents 2024年第2期64卷

作者： Yi-Chyi Lai Luo-Wei Lin Yu-Lin Lee Department of Internal Medicine Chung Shan Medical University Hospital Taichung Taiwan Department of Microbiology and Immunology School of Medicine Chung Shan Medical University Taichung Taiwan PhD Program in Medical Biotechnology Institute of Genomics and Bioinformatics National Chung-Hsing University Taichung Taiwan School of Medicine Chung Shan Medical University Taichung Taiwan

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Involvement of Rho-associated kinase in neurite sprouting and amyloid beta production of rat cortical neurons cultured in insulin-free medium

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Psychogeriatrics 2003年第1期3卷

作者： Naohiko Matsumoto Yu Nakamura Yujiro Kashiwagi Ryota Hashimoto Takashi Kudo Toshihisa Tanaka Kazuhiro Shinosaki Masatoshi Takeda Division of Psychiatry and Behavioral Proteomics Department of Post-Genomics and Diseases Course of Advanced Medicine Osaka University Graduate School of Medicine Osaka Department of Psychiatry Nara Medical University Nara Department of Psychosomatic Medicine and Psychiatry Kansai Rosai Hospital Hyogo Japan and Section on Molecular Neurobiology Mood and Anxiety Disorder Program National Institute of Mental Health National Institutes of Health Bethesda MD USA

Background: Abnormal sprouting of neurites is one of the neuropathological features of Alzheimer's disease. The mechanism of neurite sprouting of cultured neurons remains unknown. Among small guanosine triphosphate binding proteins, participation of the Rho family has been speculated. Methods: The involvement of Rho-associated kinase in neurite sprouting and in amyloid beta (Αβ) production was investigated in primary cultured rat cortical neurons using morphometric analysis, immunohistochemistry and ELISA assay. Results: In a serum-free medium, Y-27632, a Rho-associated kinase specific inhibitor, was found on the neurite outgrowth; however, there was no effect of Y-27632 on Neurobasal/B27. A custom medium without insulin was prepared because insulin potentially influences neurite formation. In the insulin-free medium, 10 µmol/L Y-27632 appeared to promote neurite outgrowth, showing significant increases in neurite length and in the number of neurite terminals. Y-27632 generated abnormal neurites, which were positively stained by both MAP2 and neurofilament-L. Furthermore, the effect of Y-27632 on Αβ production in primary cultured rat cortical neurons was investigated. Inhibition of Rho-associated kinase increased the ratio of Αβ 42 /40+42. Conclusion: Our findings indicated that Rho-associated kinase might be involved not only in neurite sprouting, but also in Αβ production in primary cultured neurons. Considering these two effects, inhibition of Rho-associated kinase activity might be involved in the pathology of Alzheimer's disease.

关键词： Alzheimer's disease amyloid beta insulin neurite sprouting primary cultured neurons Rho

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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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Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women

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Gynecologic oncology 2019年第2期153卷 343-355页

作者： Kate Lawrenson Fengju Song Dennis J Hazelett Siddhartha P Kar Jonathan Tyrer Catherine M Phelan Rosario I Corona Norma I Rodríguez-Malavé Ji-Hei Seo Emily Adler Simon G Coetzee Felipe Segato Marcos A S Fonseca Christopher I Amos Michael E Carney Georgia Chenevix-Trench Jiyeob Choi Jennifer A Doherty Weihua Jia Gang J Jin Byoung-Gie Kim Nhu D Le Juyeon Lee Lian Li Boon K Lim Noor A Adenan Mika Mizuno Boyoung Park Celeste L Pearce Kang Shan Yongyong Shi Xiao-Ou Shu Weiva Sieh Pamela J Thompson Lynne R Wilkens Qingyi Wei Yin L Woo Li Yan Beth Y Karlan Matthew L Freedman Houtan Noushmehr Ellen L Goode Andrew Berchuck Thomas A Sellers Soo-Hwang Teo Wei Zheng Keitaro Matsuo Sue Park Kexin Chen Paul D P Pharoah Simon A Gayther Marc T Goodman Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center 8700 Beverly Boulevard Suite 290W Los Angeles CA USA Center for Bioinformatics and Functional Genomics Cedars Sinai Genomics Core Cedars-Sinai Medical Center Los Angeles CA USA. Electronic address: kate.lawrenson@***. National Clinical Research Center for Cancer Tianjin Medical University Cancer Institute and Hospital Tianjin China Department of Epidemiology and Biostatistics Key Laboratory of Cancer Prevention and Therapy Tianjin China. Center for Bioinformatics and Functional Genomics Cedars Sinai Genomics Core Cedars-Sinai Medical Center Los Angeles CA USA. Department of Oncology Centre for Cancer Genetic Epidemiology University of Cambridge Strangeways Research Laboratory Cambridge UK. Department of Gynecologic Oncology Moffitt Cancer Center Tampa FL USA Department of Cancer Epidemiology Moffitt Cancer Center Tampa FL USA. Center for Bioinformatics and Functional Genomics Cedars Sinai Genomics Core Cedars-Sinai Medical Center Los Angeles CA USA. Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA. Department of Preventive Medicine University of Southern California Keck School of Medicine 1450 Biggy Street Los Angeles CA USA. Department of Genetics Ribeirão Preto Medical School University of São Paulo 14049-900 Brazil. Institute for Clinical and Translational Research Department of Medicine Baylor School of Medicine HoustonTX USA. Department of Obstetrics and Gynecology John A. Burns School of Medicine University of Hawaii Honolulu HI USA. Genetics and Computational Biology Department QIMR Berghofer Medical Research Institute 300 Herston Road Herston QLD 4006 Australia. Department of Preventive Medicine Seoul National University College of Medicine Seoul Republic of Korea Cancer Research Institute Seoul National University Seoul Republic of Korea Department of Biomedical Science Graduate School Seoul National Un

OBJECTIVE:Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS:Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS:At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10). SNP rs6902488 at 6p25.2 (r = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10). CONCLUSION:While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

关键词： Asian ancestry Enhancer Epithelial ovarian cancer Gene regulation Genome-wide association study eQTL

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