S E R IV T E C D U R R O T S I S D B O D E C I T A N L O E R R H C D N F A O E Y S D A U E T S S I D S C I Y R M A O N - I O T M L L U U M P MULTI-OMICS STUDY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND RELATED DISORDERS I va n a P r o k I ć I va n a P r o k I ć Multi-omics Study of Chronic Obstructive Pulmonary Disease and Related Disorders Ivana Prokić Acknowledgements The work described in this thesis was conducted at the Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. The work presented in this thesis was supported by grant number 4.1.13.007 of Lung Foundation Netherlands (Longfonds), Biobanking and Biomolecular Resources arship. Research Infrastracture (BBMRI)-NL (184.021.007), Corbell, and by ERAWEB schol- The Erasmus Rucphen Family study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013)/ grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Orga Framework Programme (no. QLG2-CT-2002-01254). The Rotterdam Study is funded - nization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and ists, researchers, institutions and funders of all other studies from this thesis are the Municipality of Rotterdam. All study participants, general practitioners, special- appreciatively acknowledged. ment of Epidemiology, Erasmus Medical Center, Rotterdam and Erasmus University The publication and printing of this thesis was financially supported by: Depart- Rotterdam. Cover design: Slobodanka Nišić and Ivana Prokić Layout: Optima Grafische Communicatie ©Printing: Optima Grafische Communicatie ISBN: 978-94-6361-290-6 Ivana Prokić, 2019 For articles published or accepted for publication, the copyright has been trans ferred to the respective publisher. No part of this thesis may be reproduced, stored - in a retrieval system or transmitted in any form or by any means without the per mission of the author, or, when appropriate, from the publishers of the manuscript. - Multi-omics Study of Chronic Obstructive Pulmonary Disease and Related Disorders Multi-omics studie van Chronische Obstructieve Longziekte en verwante stoornissen Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de Prof.rector dr. R.C.M.E. magnificus Engels en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag, 4 september 2019 om 11:30 uur door Ivana Prokić (geboren Nedeljković) geboren te Belgrado, Serviё Promotiecommissie Promotor: Prof. dr. ir. C.M. van Duijn Overige leden: Prof. dr. H.M. Boezen Prof. dr. J. van Meurs Prof. dr. G.G. Brusselle Copromotor: Dr. N. Amin Paranimphen: Desana Kocevska Ashley van der Spek Za moju večitu pordršku, Jovanu, Marka, Anđu i Miška; I moju novu snagu, Petra i Lenku. Table of coNTeNTs chapter 1 General introduction 11 chapter 2 Omics studies of COPD and lung function 31 2.1 33 A genome-wide linkage study for chronic obstructive rare candidate variants pulmonary disease in a Dutch genetic isolate identifies novel 2.2 51 through epigenetics and transcriptomics Understanding the role of the chromosome 15q25.1 in COPD 2.3 73 methylation and gene expression COPD GWAS variant at 19q13.2 in relation with DNA 2.4 93 DNA methylation is associated with levels of lung function in never-smokers chapter 3 Omics studies of COPD comorbidity: 113 asthma, depression and systemic effects 3.1 115 the risks of asthma and COPD across the life course New-born DNA-methylation, childhood lung function, and 3.2 137 Chronic obstructive pulmonary disease A cross-omics integrative study of metabolomic signature of 3.3 Genetic correlation of Chronic Obstructive Pulmonary 157 3.4 167 Disease and non-pulmonary comorbidity DNA methylation signatures of depressive symptoms identified in a large multi-ethnic meta-analysis of epigenome-wide studies chapter 4 General Discussion 187 4.1 Findings of this thesis 189 4.2 Methodological considerations 193 4.3 Potential implications and future directions 199 chapter 5 Summary/samenvatting 207 chapter 6 Appendix 215 6.1 217 6.2 219 Acknowledgements 6.3 PhD portfolio 221 About the author 6.4 223 List of publications PublIcaTIoNs aND maNuscrIPTs IN ThIs ThesIs chapter 2.1 Ivana Nedeljković , Natalie Terzikhan, Judith M. Vonk, Diana A. van der Plaat, Lies Lahousse, Cleo C. van Diemen, Brian D. Hobbs, Dandi Qiao, Michael H. Cho, Guy G. A genome-wide linkage study for chronic obstructive pulmonary disease in a Dutch Brusselle, Dirkje S. Postma, H. MarikeBoezen, Cornelia M. van Duijn, Najaf Amin. genetic isolate identifies novel rare candidate variants. Frontiers in Genetics, 2018 Apr 19; 9:133; doi: 10.3389/fgene.2018.00133. chapter 2.2 Ivana Nedeljković , Elena Carnero-Montoro, Lies Lahousse, Diana A. van der Plaat, Kim de Jong, Judith M. Vonk, Cleo C. van Diemen, AlenFaiz, Maarten van den Berge, Ma’enObeidat, Yohan Bossé, David C. Nickle, BIOS consortium, Andre G. Uitterlin- Understanding the role of the den, Joyce B.J. van Meurs, Bruno H.C. Stricker, Guy G. Brusselle, Dirkje S. Postma, chromosome 15q25.1 in COPD through epigenetics and transcriptomics. European H. MarikeBoezen, Cornelia M. van Duijn, Najaf Amin. Journal of Human Genetics, 2018 Feb 8; 26:709–722; doi: 10.1038/s41431-017-0089-8. chapter 2.3 Ivana Nedeljković , Lies Lahousse, Elena Carnero-Montoro, AlenFaiz, Judith M. Vonk, Kim de Jong, Diana A. van der Plaat, Cleo C. van Diemen, Maarten van den Berge, Ma’enObeidat, Yohan Bossé, David C. Nickle, BIOS Consortium, Andre G. COPD GWAS variant Uitterlinden, Joyce B.J. van Meurs, Bruno H.C. Stricker, Guy G. Brusselle, Dirkje S. at 19q13.2 in relation with DNA methylation and gene expression. Postma, H. MarikeBoezen, Cornelia M. van Duijn, Najaf Amin. Human Molecular Genetics, 2018 Jan 15; 27(2):396-405; doi: 10.1093/hmg/ddx390. chapter 2.4 Maaike de Vries, Ivana Nedeljković , Diana A. van der Plaat, Lies Lahouse, Guy G. DNA methylation is associated with lung function levels in never-smokers. Brusselle, Alexandra Zhernakova, Cornelia M. van Duijn, Judith M. Vonk, H. Marike- Manuscript submitted for publication. Boezen. chapter 3.1 Ivana Nedeljković Herman T. den Dekker*, Kimberley Burrows*, Janine F. Felix*, Lucas A. Salas, , Jin Yao, Sheryl L. Rifas-Shiman, Carlos Ruiz-Arenas, N. Amin, Mariona Bustamante, Dawn L. DeMeo, A. John Henderson, Caitlin G. Howe, Marie-France Hi- vert, M. Arfan Ikram, Johan C. de Jongste, Lies Lahousse, Pooja R. Mandaviya, Joyce B. van Meurs, MarionaPinart, Gemma C. Sharp, Lisette Stolk, André G. Uitterlinden, Josep # # #. New-born M. Anto, Augusto A. Litonjua, Carrie V. Breton, Guy G. Brusselle, Jordi Sunyer, George DNA-methylation, childhood lung function, and the risks of asthma and COPD across Davey Smith, Caroline L. Relton , Vincent W.V. Jaddoe , LiesbethDuijts the life course. Eur Respir J. February 2019:1801795. doi:10.1183/13993003.01795-2018 *first authors contributed equally #last authors contributed equally chapter 3.2 Ivana Nedeljković , Lies Lahousse, Maaike de Vries, Jun Liu, Marita Kalaoja, Judith M. Vonk, Diana A. van der Plaat, Cleo C. van Diemen, Ashley van der Spek, Alexandra Zhernakova, Jingyuan Fu, Mohsen Ghanbari, Mika Ala-Korpela, Johannes Kettunen, A Aki S. Havulinna, Markus Perola, VeikkoSalomaa, Lars Lind, Johan Ärnlöv, Bruno H.C. cross-omics integrative study of metabolomic signature of Chronic obstructive pulmo- Stricker, Guy G. Brusselle, H. MarikeBoezen, Cornelia M. van Duijn, Najaf Amin. nary disease. Manuscript submitted for publication. chapter 3.3 Ivana Nedeljković Genetic , Maaike de Vries, Judith M. Vonk, Lies Lahousse, Bruno H.C. correlation of Chronic Obstructive Pulmonary Disease and non-pulmonary comorbid- Stricker, Guy G. Brusselle, Najaf Amin, Marike Boezen, Cornelia M. van Duijn. ity. Manuscript in preparation for submission. chapter 3.4 Ivana Nedeljković Olivera Jovanova*, *, Derek Spieler *, Rosie M. Walker*, Chunyu Liu*, Michelle Luciano*, Jan Bressler, Jennifer Brody, Amanda J. Drake, Kathryn L. Evans, Rahul Gondalia, Sonja Kunze, Brigitte Kuhnel, Jari Lahti, Rozenn N. Lemaitre, Riccardo E. Marioni, Brenton Swenson, Jayandra Jung Himali, Hongsheng Wu, Yun Li, Allan F. McRae, Tom C. Russ, James Stewart, Zhiying Wang, Guosheng Zhang, Karl-Heinz Ladwig, Andre G. Uitterlinden, Xiuqing Guo, Annette Peters, KatriRäik- könen, John M. Starr, Melanie Waldenberger, Naomi R. Wray, Whitsel A. Eric, Nona Sotoodehnia, Sudha Seshadri, David J. Porteous, Joyce van Meurs, Thomas H. Mosley, Andrew M. McIntosh, Michael M. Mendelson, Daniel Levy, Lifang Hou, Johan G. Er- DNA methylation signatures of depressive symptoms in middle-aged and el- iksson, Myriam Fornage, Ian J. Deary, Andrea Baccarelli, Henning Tiemeier, Najaf derly persons: meta-analysis of multiethnic epigenome-wide studies. Amin. JAMA Psychiatry. 2018;75(9):949-959. doi:10.1001/jamapsychiatry.2018.1725 *first authors contributed equally Chapter 1 Introduction Introduction COPD 1 disease, characterized by chronic and progressive course. It’s pathology involves Chronic obstructive pulmonary disease (COPD) is the most1 common respiratory chronic inflammatory response of the airways, overproduction of mucus (resulting in chronic bronchitis), parenchymal tissue destruction (resulting in emphysema) This leads to air trapping in the lungs, sputum production, obstructed exhalation,2 and abnormal repair defence mechanisms (resulting in small airway fibrosis). dyspnoea and cough, common symptoms associated with COPD.