Aetiology of Depression: Insights from epidemiological and genetic research Olivera Story-Jovanova Acknowledgments: Financial support for the publication of this thesis by the Department of Epidemiology of the Erasmus MC, is gratefully acknowledged. ISBN: 978-94-6233-909-5 Cover: Concept by Olivera Story-Jovanova, design by Chris van Wolferen-Ketel, photography by Michal Macku. Layout: Gildeprint, Enschede. Printing: Gildeprint, Enschede. © Olivera Story-Jovanova, 2018 For all articles published, the copyright has been transferred to the respective publisher. No part of this thesis may be stored in a retrieval system, or transmitted in any form or by any means, without written permission from the author or, when appropriate, from the publisher. Aetiology of Depression: Insights from epidemiological and genetic research Etiologie van depressie: Inzichten vanuit de epidemiologisch en de genetisch onderzoek Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof. dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op 4 April 2018 om 15:30 uur door Olivera Story-Jovanova geboren te Skopje, Macedonia PROMOTIECOMMISSIE Promotor Prof. dr. H. Tiemeier Overige leden Prof. D. Boomsma Prof. K. Berger Prof. C. van Duijn Copromotor Dr. N. Amin Paranimfen Ayesha Sajjad Dina Atlas For my husband, children, sister, parents, grandparents, my parents in law and all you who believed in me. You are a gift of unconditional love, acceptance, joy and wisdom. I am thankful for that! ACKNOWLEDGEMENTS The research described in this thesis was performed within the frame work of the Rotterdam Study. The contribution of participants, the staff from the Rotterdam Study and the participating general practitioners, and pharmacists is gratefully acknowledged. The Rotterdam Study is supported by the Erasmus Medical Center and the Erasmus University, Rotterdam, the Netherlands; the Organization 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 the Municipality Rotterdam. The research was supported by a Netherlands Organization for Scientific Research grant (NOW- ZonMw VIDI grant no. 017.106.370) awarded to prof. H. Tiemeier and by the European Commission – ERAWEB Grant (grant no. 2011-2586/001-001-EMA2) awarded to O. Jovanova, MD. CONTENTS Chapter 1 General introduction 9 Chapter 2 Biomarkers for depression 21 Chapter 2.1 Vitamin D serum levels and depression in the elderly 23 Chapter 2.2 Inflammatory markers and depression in the elderly 41 Chapter 3 The genetics of depression 63 Chapter 3.1 A rare Asn396Ser variant in the LIPG gene associated with depressive symptoms 65 Chapter 3.2 Nonsynonymous variation in NKPD1 increases depressive symptoms 85 Chapter 4 The epigenetics of depression 121 Chapter 4.1 DNA-methylation signatures and depressive symptoms 123 Chapter 5 Physical health factors for depression 203 Chapter 5.1 Multiple episodes of late-life depression and cognitive decline 205 Chapter 5.2 Myocardial infarction and the long-term risk for depression 223 Chapter 6 General discussion 255 Chapter 7 Summary 281 Chapter 8 Addendum 287 Chapter 8.1 PhD Portfolio 289 Chapter 8.2 Publications and manuscripts 293 Chapter 8.3 Word of thanks 297 Chapter 8.4 About the author 305 MANUSCRIPTS UPON WHICH THIS THESIS IS BASED Chapter 2.1: Jovanova O, Aarts N, Noordam R, Carola-Zillekens M, Hofman A, Tiemeier H. Vitamin D serum levels are cross-sectionally but not prospectively associated with late-life depression. ACTA Psychiatrica Scandinavica. 2017 Mar; 135(3):185-194. Chapter 2.2: Zalli A, Jovanova O, Hoogendijk WJ, Tiemeier H, Carvalho LA. Low-grade inflammation predicts persistence of depressive symptoms. Psychopharmacology. 2016 May; 233(9):1669-78. Chapter 3.1: Amin N, Jovanova O, Adams HH, Dehghan A, Kavousi M, Vernooji MW, Peeters RP, de Vrij FM, van der Lee SJ, van Rooij JG, van Leeuwen EM, Chaker L, Demirkan A, Hofman A, Brouwer RW, Kraaij R, Willems van Dijk K, Hankemeier T, van Ijcken WF, Uitterlinden AG, Niessen WJ, Franco OH, Kushner SA, Ikram MA, Tiemeier H, van Duijn CM. Exome- sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms. Molecular Psychiatry. 2017 Apr; 22(4):537- 543. Chapter 3.2: Amin N, Belonogova NM, Jovanova O, Brouwer RW, van Rooij JG, van den Hout MC, Svishcheva GR, Kraaij R, Zorkoltseva IV, Kirichenko AV, Hofman A, Uitterlinden AG, van IJcken WF, Tiemeier H, Axenovich TI, van Duijn CM. Nonsynonymous Variation in NKPD1 Increases Depressive Symptoms in the European Populations. Biological Psychiatry. 2017 Apr; 81(8):702-707. Chapter 4.1: Jovanova O, Nedeljkovic I, Lemaitre R, Brody J, Swenson B, Liu Ch, Hongsheng, Lahti J, Kunze S, Kuhnel B, Luciano M, Deary IJ, Marioni R, Walker RM, Evans KL, Wang Z, Gondalia R, Levy D, Seshadri S, Karl-Heintz L, Waldenberg M, McRae AF, Starr JM, Wray N, Bressler J, Mosley TH, Guo X, Sotoodehnia N, Mendelson MM, Peters A, Russ TC, McIntosh AM, Porteous DJ, Fornage M, Whitsel AE, Tiemeier H, Amin N. DNA methylation signatures of depressive symptoms identified in a large multi-ethnic meta-analysis of epigenome-wide studies. Under review. Chapter 5.1: Jovanova O, Wolters FJ, Ikram MA, Tiemeier H, Schmitz N. DNA methylation signatures of depressive symptoms identified in a large multi-ethnic meta-analysis of epigenome-wide studies. Under review. Chapter 5.2: Jovanova O, Luik AI, Leening MJG, Noordam R, Aarts N, Hofman A, Franco OH, Dehghan A, Tiemeier H. The long-term risk of recognized and unrecognized myocardial infarction for depression in older men. Psychological Medicine. 2016 Mar; 46(9):1951-60. CHAPTER 1 General Introduction INTRODUCTION Have you ever felt depressed? The answer to this question is usually “YES” and this is not unreasonable since most of us have felt depressed once or more in our life-time. Typically, “feeling depressed” or “feeling BLUE” is not more than the well-accepted low mood or just being temporarily unhappy. On the contrary, clinical depression is a serious neuropsychiatric mood disorder that has a leading role in the global burden of diseases causing much of the disability world-wide.1,2 Individuals suffering from depression have feelings of guilt, helplessness, hopelessness, are occupationally impaired, often have desire for social withdrawal, suffer from sleep and concentration disturbances, have a loss of interest in life-pleasures and almost all other activities, and suffer from a loss of appetite and sex drive.3 This extensive list of depressive symptoms can also include daily experience of suicidal thoughts that can result in a suicidal act.3 As a matter of fact, depression is a complete contrast to the beauty of the colour BLUE; a colour that awakens feelings of tranquillity, stability and inspiration (Yves Klein dedicated a life-time of work to the colour blue: “Blue Revolution”). ®“Blue Monochrome (anthropometry)” - Yves Klein 1928-1962 R1 In the last 15 years a number of successful campaigns took place around the world to raise the R2 awareness for depression.4,5 One of the main goals of such campaigns was to reduce the stigma R3 of depression and to clarify the differences between being sad and suffering from depressive R4 disorders. These goals were mostly achieved and the knowledge over depressive illness among R5 the public has increased. More persons have some understanding of the physical and mental R6 exhaustion caused by this medical illness. However, the reality is: “We still do not completely R7 understand all aspects of depression”! Even though depression may not be an enigma anymore, R8 there are many core questions asked by lay people, medical doctors, and academic experts that R9 remain unclear. One such question is “What actually causes depression?”! Briefly, this thesis is an R10 attempt to unravel some aspects of the aetiology of depression. R11 R12 IS DEPRESSION the DIABETES OF the BRAIN or a DEMONIC POSSESSION? A brief historical R13 aspect R14 R15 I would first like to quote the famous Chinese philosopher Confucius who said “Study the past R16 if you would define the future”. Indeed, if we try to obtain new insights into the aetiology of R17 depression and draw conclusions on this illness; and finally define some future perspectives for a R18 better understanding of depression, we should certainly understand the history of this disorder. R19 Throughout history, depression transformed from the old concept of melancholia to the current R20 concept of depression which is mainly viewed as a multifactorial behavioural mental disorder. This R21 transition did not occur all of a sudden, but throughout the centuries, many philosophers and R22 scientists struggled explaining depression while facing a lot of controversies. This explains why R23 studying depression and its aetiology is a great challenge even today.6 R24 R25 It was in the ancient times that the first theories were postulated to define and explain depression: R26 Melancholia, a condition characterized by fear, loss-of appetite, and sleeplessness. The humoral R27 theory proposed by Hippocrates (370-460 B.C), the father of medicine; explained melancholia.7 R28 According to the humoral concept melancholia was a condition caused by disequilibrium between R29 the four humors and more specifically by an increase in the black bile.7 The core of this theory R30 was slightly modified and edited during the centuries to come. It took almost 2,500 years to R31 move from Hippocrates melancholia to Emil Kraepelin’s concept of depression (1856 –1926). He R32 was the first scientist to propose the use of the term depression, but what made it so difficult to R33 progress to defining depression as a disorder?8 R34 R35 In order to define this medical condition as a disorder, depression must be associated with specific R36 symptoms and signs that are caused by external factors and internal dysfunctions.