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Assessment of the Role of the Thymic Transcriptome in Genetic Predisposition to Autoimmune Diseases

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Assessment of the Role of the Thymic Transcriptome in Genetic Predisposition to Autoimmune Diseases Assessment of the role of the thymic transcriptome in genetic predisposition to autoimmune diseases Thesis for the degree of Philosophiae Doctor (PhD) By Ingvild Synnøve Matre Gabrielsen 2018 Department of Medical Genetics, Oslo Univers ity Hospital, Ullevå l, Oslo Faculty of Medicine, University of Oslo 1 © Ingvild Synnøve Matre Gabrielsen, 2019 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-399-6 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. 2 Table of Contents Acknowledgement ...................................................................................................................... 5 Abbreviations ............................................................................................................................. 6 List of publications ..................................................................................................................... 8 1. Introduction ............................................................................................................................ 9 1.1 Autoimmune diseases: general features and epidemiology ...................................................... 9 1.2 Pathogenesis.......................................................................................................................11 1.3 Etiology .............................................................................................................................13 1.4 Genetics of complex diseases...............................................................................................13 1.4.1 Human genetic variation and linkage disequilibrium .......................................................13 1.4.2 Genetic association studies ............................................................................................15 1.4.3 Functional role of genetic variants .................................................................................16 1.4.4 Expression quantitative trait loci ....................................................................................20 1.5 The thymus ........................................................................................................................22 1.5.1 Thymocytes develop and go through several selection points in thymus ...........................22 1.5.2 Thymic antigen presenting cells in the medulla ...............................................................24 2. Aims ..................................................................................................................................... 27 3. Summary of papers ............................................................................................................... 28 3.1 Paper I ...............................................................................................................................28 3.2 Paper II ..............................................................................................................................29 3.3 Paper III .............................................................................................................................30 4. Methodological considerations............................................................................................. 31 4.1 Study population.................................................................................................................31 4.2 Thymic tissue preparation....................................................................................................32 4.2.1 Cell separation..............................................................................................................32 4.2.3 DNA and RNA extraction .............................................................................................36 4.3 Selection and genotyping of AID risk variants ......................................................................37 4.4 Gene expression measurement .............................................................................................38 3 4.4.1 Microarray ...................................................................................................................38 4.4.2 RNA Sequencing ..........................................................................................................38 4.5 Quality Control of the data ..................................................................................................42 4.6 Statistics.............................................................................................................................44 4.7 The Human Protein Atlas ....................................................................................................47 5. Discussion............................................................................................................................. 50 5.1 Are the thymic APCs affected by the AID-eQTLs?...............................................................50 5.2 The individual eGenes.........................................................................................................52 5.1.1 ERAP2 ........................................................................................................................52 5.1.2 ERAP1 ........................................................................................................................54 5.1.3 SIRPG.........................................................................................................................55 5.1.4 FCRL3.........................................................................................................................55 5.1.5 RNASET2....................................................................................................................56 5.1.6 SYS1 ...........................................................................................................................56 5.1.7 NPIPB8 .......................................................................................................................57 5.1.8 C2orf74 .......................................................................................................................57 5.1.9 AJ006998.2 ..................................................................................................................58 5.2 Are the eGenes involved in any specific pathways?...............................................................58 5.3 Have we found all the AID-eQTLs?.....................................................................................59 5.4 The location of regulatory eSNPs relative to their eGenes......................................................59 6 Conclusions and future perspectives........................................................................................60 References ................................................................................................................................ 62 Errata......................................................................................................................................... 70 4 Acknowledgement This work has been carried out at the Department of Medical Genetics, Oslo University Hospital Ullevål and University of Oslo during the period 2012-2018. I would like to thank the head of the Department, Dag Undlien, for an excellent research environment. I am very thankful for the research grant I received from the Norwegian research council. I am especially grateful to my eminent, main supervisor Benedicte A. Lie for her guidance through the complex field of genetics. Thank you Benedicte, for sharing so much of your impressive knowledge and giving me so many good advices (the best one was definitely “one thing at a time, as Alfie Atkins father said”). You are always available, optimistic and have so much enthusiasm, which really encouraged and motivated me to carry on. I feel privileged to have been part of your research group these five years. Siri T. Flåm, you deserve a special thanks, you are the Duracell bunny of the group. You have an impressing working capacity and have helped me so much with the thymic tissue in the lab which has required many late nights. Hanna Helgeland, you deserve special thanks too, for all the programming you did in these projects. I learned so much from studying your scripts; it really opened my eyes for programming. My amazing colleagues, Marte K. Viken, Silja S. Amundsen, Arvind Sundaram, Hans Christian Dalsbotten Aass, Helle Akselsen, and Kris tian Holm thank you for sharing your knowledge, your participation in scientific discussions, all your help in the lab, with the data and all the advice you have given me in the projects and in the manuscripts. I am also very grateful to Harald Lindberg, all the patients, Tone and all the nurses and surgeons at Rikshospitalet who provided us with the thymic tissues. A big thanks to all the other members of my group who always contribute to such a nice working environment: Kari Guderud, Line Sunde, Fatima Heinicke, Asgeir Lande, Eva Kr i s ti ne Henrik s en, Maria Vig eland and Fatemeh Kaveh. Lastly, thanks to Yl va Kai s er and Cara Bray who made me understand that scientific conference is not only about learning, but also about networking and making friends. Finally, I would like to thank my family and friends, and especially to Svenn-Arne Dragly. Thank you
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