Cindy Boer

Summary | 279 7 Summary Osteoarthritis is the most common chronic degenerative joint disease worldwide, and has been present throughout history, evidenced by fossilized findings of osteoarthrit- ic joints. Making Osteoarthritis one of the world’s oldest diseases, and yet no curative treatments are available. The aim of this thesis is to identify novel genes involved in osteoarthritis, in order to gain greater insight into the pathology of osteoarthritis and bring possible preventive or curative treatments closer for one of the world’s oldest disease. Chapter 1 gave an introduction of osteoarthritis and it’s long history. Also, key concepts in genetics, genetic epidemiology research and epigenetics were covered. Chapter 1.2 , delved deeper into the role that epigenetics play in osteoarthritis research and pathol- ogy. In Chapter 2 results of two genome-wide association studies using two different types of osteoarthritis phenotypes were presented. Although, these studies had a relatively small sample size (n≤10,000) both studies robustly identify novel osteoarthritis associ- ated loci. Using follow-up translational research, novel candidate genes for osteoarthri- tis therapeutic development were identified. Demonstrating and confirming the poten- tial for novel insight into the genetic architecture of osteoarthritis by using biologically meaningful phenotypes (stratified or endophenotypes). Chapter 2.1 showed the use of minimal joint space width (mJSW) as an en- dophenotype for hip cartilage thickness. Using this osteoarthritis endophenotype four novel genetic loci associated with cartilage thickness and hip osteoarthritis were identi- fied. In addition, two known osteoarthritis associated loci were replicated, (rs2864419) DOT1L and (rs109481947) SUPT3H-RUNX2 . Systematic prioritization using diverse lines of evidence pointed to likely causal genes for the identified loci: RUNX2, TGFα, PIK3R1, SLBP/FGFR3, DOT1L/GADD45B and TREH/DDX6 . Of these TGFα, PIK3R1 and FGFR3 were differentially expressed between osteoarthritis lesioned and non-lesioned cartilage. In Chapter 2.2 three hand osteoarthritis phenotypes were created based on the pattern and severity of radiographic osteoarthritis in the hand joints: thumb osteoar- thritis severity (klsum), finger osteoarthritis severity (KLsum) and hand osteoarthritis severity (KLsum). Two known hand osteoarthritis associated loci were replicated and