Cindy Boer

General Discussion | 255 6 The overall objective of this thesis was to gain greater insight into the pathology of os- teoarthritis, with the hope to bring possible preventive or curative treatments closer for one of the world’s oldest diseases. In the previous chapters we have presented novel ge- netic loci, genes, biological pathways and risk factors for osteoarthritis. There the main findings, limitations and implications of each study were discussed. In this chapter, all findings presented in this thesis are brought together, considerations are addressed and suggestions for future osteoarthritis research are given. Osteoarthritis associated genetic variation In this thesis, genome-wide association studies (GWASs) were used to identify novel ge- netic loci associated with osteoarthritis, in order to identify novel genes and biological pathways involved in osteoarthritis pathology. Prior to the start of this thesis the num- ber of identified osteoarthritis associated loci was severely limited, only 17 loci were known[1], a far cry of the hundreds predicted to be involved . Currently 148 osteoarthri- tis associated loci have been reported. In Figure 1 all currently reported genome-wide osteoarthritis associated SNVs are listed, those mentioned in this thesis are highlighted. GWAS size matters and more is needed The success of GWASs to robustly identify associated genetic loci, is dependent on sever- al factors; (i) the phenotype studied must have a genetic component, (ii) the quality and number of genetic variants that are used in the GWAS, (iii) the sample size (power) of the GWAS, (iv) and the heterogeneity of the studied phenotype[2]. Especially sample size is one of the most limiting factors for statistical power in GWAS[2]. This is demonstrated in Chapter 4 . Before this thesis, the largest osteoarthritis GWAS consisted of ~7,000 osteoarthritis cases (~42,000 controls) and identified five loci[1]. Now the largest oste- oarthritis GWAS effort, the Genetics of Osteoarthritis (GO) consortium, (~180.000 cas- es and ~600.000 controls) identified 100 osteoarthritis associated loci ( Chapter 4 ). It is this increase in sample size, driven by the availability of large scale biobanks, such as the UKbiobank, and increased (inter)national collaboration efforts[9-11], that has caused the increase in associated osteoarthritis loci. Yet, despite these advances and progress made by the GO consortium, the proportion of genetic heritability explained by the found SNVs for osteoarthritis is still relatively low, ranging between 6% for hand osteoarthritis to 21% for hip osteoarthritis and total hip replacement ( Table 1 ) . Indi- cating that still much of the osteoarthritis genetics, remains undiscovered.