Osteoarthritis: Genetics and Phenotypes in All Their Complexity Cindy Germaine Boer
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Osteoarthritis: genetics and phenotypes in all their complexity Cindy Germaine Boer The works described in this thesis was conducted at the department of Internal Medicine at the Erasmus MC University Medical Center Rotterdam, the Netherlands. The Rotterdam study is funded by Erasmus MC University Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMW); the Research institute for Diseases in the elderly (RIDE); the Dutch Ministry of Education, Culture and Science; the Dutch Ministry of Health, Welfare and sports; the European Commission (DG XII); and the municipality of Rotterdam. ISBN: 978-94-6416-105-2 Cover Design: Cindy G. Boer Design: Cindy G. Boer and Ridderprint Illustrations: Cindy G. Boer Layout and printing: Ridderprint © Cindy Germaine Boer | 2020 All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without prior written permission of the author, or, the scientific journal in which parts of the book have been published. Osteoarthriti s: geneti cs and phenotypes in all their complexity Artrose: geneti ca en fenotypen in al hun complexiteit Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rott erdam op gezag van de rector magnifi cus Prof. Dr. R.C.M.E. Engels en volgens besluit van het College voor Promoti es. De openbare verdediging zal plaatsvinden op dinsdag 15 december 2020 om 13:30 uur Door Cindy Germaine Boer geboren te Sliedrecht Promotiecommissie Promotor: Prof. Dr. A.G. Uitterlinden Overige Leden: Prof. Dr. G. van Osch Prof. Dr. M.A. Ikram Prof. Dr. E. Zeggini Co-promotor: Dr. J.B.J. van Meurs Paranimfen: Justin D. Boer, BSc. Joost A.M. Verlouw, BSc. Contents Chapter 1 General Introduction 1.1 General Introduction 11 1.2 Role of Epigenetics in bone and cartilage disease 31 Chapter 2 Phenotypes of Osteoarthritis 2.1 Novel Genetic Variants for Cartilage Thickness and Hip Osteoar- 67 thritis 2.2 Hand Phenotypes Identify WNT9A as Novel Gene Associated with 93 Thumb Osteoarthritis Chapter 3 Hand Osteoarthritis genetics 3.1 Genome-Wide Association and Functional Studies Identify a Role 117 for Matrix-Gla Protein in Osteoarthritis of the Hand 3.2 Vitamin K Antagonist Anticoagulant Usage is Associated with In- 133 creased Incidence and Progression of Osteoarthritis Chapter 4 Large Scale Osteoarthritis Genetics 4.1 Deciphering Osteoarthritis Genetics Across 826,690 Individuals 159 from 9 populations Chapter 5 Osteoarthritis and the microbiome 5.1 Compositional and Functional Differences in Gut Microbiota of 203 Healthy Children and Adults: the Rotterdam Study and Generation R Study 5.2 Intestinal Microbiome Composition and its Relation to Joint Pain 229 and Inflammation Chapter 6 General Discussion 253 Chapter 7 Summary / Nederlandse Samenvatting 277 Appendices About the author/Over de auteur 297 PhD portfolio 301 List of publications 309 Acknowledgements/Dankwoord 317 A PhD is not a Journey, it’s a Quest. Alistair McCulloch A PhD is not a Journey, it’s a Quest. Alistair McCulloch Chapter 1 General Introduction Chapter 1.1 General Introduction 12 | Chapter 1.1 The problem Osteoarthritis is one of the world’s oldest diseases, and yet no curative treatments are available. Osteoarthritis is the most common chronic degenerative joint disease world- wide and has been present throughout history, evidenced by the presence of osteoar- thritis in the fossilized ankle bones of Iguanodon bernissartensis (Figure 1), the first ever recognized dinosaur species[1, 2]. Not only dinosaur fossils have been found with osteoarthritis, also early bird ancestor (Caudipteryx)[3], marsupial (Diprotodon) [4], and mammal (Glyptodont Canis dirus)[5, 6] fossils are known. In fact, probably the first common ancestor to all bony vertebrates (Eutelestomi) could have been and affected by os-teoarthritis[7]. Early man was also plagued by osteoarthritis. The disease is one of the most common features seen in archeo-paleontology[8], with evidence from Neander-thals[9], early inhabitants of America[10], Egyptian mummies[11, 12], medieval citi-zens and knights[13] (Figure 1), up to the modern day where 4-5% of the entire world population has at least one joint affected by OA[2]. Symptoms of the disease are stiffness, loss of mobility and loss of function in the affected joint, with pain described as the most dominant and disabling symptom of the disease[14]. Not surprisingly, osteoarthritis is the single biggest cause for joint pain and disability worldwide[2]. Currently osteoarthritis is the third most rapidly grow- ing chronic disease worldwide[2]. Combined with the global increase in risk factors for osteoarthritis (aging, joint injury and obesity), the impact and burden of osteoarthri- tis will only continue to rise. Yet, no curative treatments for osteoarthritis are known, and much of the pathology of osteoarthritis remains a mystery. Thus, it is high time to unravel the mysteries surrounding osteoarthritis, a disease plaguing its hosts for over hundreds of millions of years. ►Figure 1: A brief Timeline of Osteoarthritis. Osteoarthritis is one of the oldest known diseases in the world; the first known bony vertebrate (Guiyu onerios) might already have had osteoarthritis. Fos- sil evidence dates back to the cretaceous (~125 Ma), and ample evidence of the disease exists in the Pleistocene, where even the H. neanderthalensis was affected by osteoarthritis. Osteoarthritis is seen throughout human history, from ancient Egypt, Greece (where Hippocrates first described signs of the disease) and medieval Europe to the modern day, however it was not until 1889 that osteoarthritis got its name. With the discovery of the helix structure of DNA, genetic research into osteoarthritis started in full; from family studies, twins studies, linkage scans and the first Genome-wide association study to the start of this thesis on “Osteoarthritis; Genotypes and phenotypes in all their complexity”. Ma: Mega annum, ka: kilo annum, annum: one year. BC: Before Christ, AD: Anno Domini General Introduction | 13 The problem Osteoarthritis is one of the world’s oldest diseases, and yet no curative treatments are available. Osteoarthritis is the most common chronic degenerative joint disease world- wide and has been present throughout history, evidenced by the presence of osteoar- thritis in the fossilized ankle bones of Iguanodon bernissartensis (Figure 1), the first 1.1 ever recognized dinosaur species[1, 2]. Not only dinosaur fossils have been found with osteoarthritis, also early bird ancestor (Caudipteryx)[3], marsupial (Diprotodon)[4], and mammal (Glyptodont, Canis dirus)[5, 6] fossils are known. In fact, probably the first common ancestor to all bony vertebrates (Eutelestomi) could have been affected by os- teoarthritis[7]. Early man was also plagued by osteoarthritis. The disease is one of the most common features seen in archeo-paleontology[8], with evidence from Neander- thals[9], early inhabitants of America[10], Egyptian mummies[11, 12], medieval citi- zens and knights[13] (Figure 1), up to the modern day where 4-5% of the entire world population has at least one joint affected by OA[2]. Symptoms of the disease are stiffness, loss of mobility and loss of function in the affected joint, with pain described as the most dominant and disabling symptom of the disease[14]. Not surprisingly, osteoarthritis is the single biggest cause for joint pain and disability worldwide[2]. Currently osteoarthritis is the third most rapidly grow- ing chronic disease worldwide[2]. Combined with the global increase in risk factors for osteoarthritis (aging, joint injury and obesity), the impact and burden of osteoarthri- tis will only continue to rise. Yet, no curative treatments for osteoarthritis are known, and much of the pathology of osteoarthritis remains a mystery. Thus, it is high time to unravel the mysteries surrounding osteoarthritis, a disease plaguing its hosts for over hundreds of millions of years. ►Figure 1: A brief Timeline of Osteoarthritis. Osteoarthritis is one of the oldest known diseases in the world; the first known bony vertebrate (Guiyu onerios) might already have had osteoarthritis. Fos- sil evidence dates back to the cretaceous (~125 Ma), and ample evidence of the disease exists in the Pleistocene, where even the H. neanderthalensis was affected by osteoarthritis. Osteoarthritis is seen throughout human history, from ancient Egypt, Greece (where Hippocrates first described signs of the disease) and medieval Europe to the modern day, however it was not until 1889 that osteoarthritis got its name. With the discovery of the helix structure of DNA, genetic research into osteoarthritis started in full; from family studies, twins studies, linkage scans and the first Genome-wide association study to the start of this thesis on “Osteoarthritis; Genotypes and phenotypes in all their complexity”. Ma: Mega annum, ka: kilo annum, annum: one year. BC: Before Christ, AD: Anno Domini 14 | Chapter 1.1 What is osteoarthritis? The first descriptions of osteoarthritis can be traced back to writings of Hippocrates (460-375 B.C.E.)[15](Figure 1). However, from these first writings until the beginnings of the 19th century, all forms of rheumatic joint diseases, including osteoarthritis, were called “gout”. In 1802, William Herben the Elder recognized osteoarthritis as a separate disease for the first time[16]. However, it took until 1889 that