Cindy Boer

General Discussion | 269 6 non-robust signals), especially for therapeutic development. Therefore, investment in deep and accurate phenotyping over ever increasing sample sizes, may be more thera- peutically beneficial in the long run. Thus, if we want to fully understand the genetic architecture and pathology of os- teoarthritis, future studies will need to invest in large scale genotyping and deep pheno- typing in globally diverse populations. Together with creating globally inclusive whole genome sequencing reference panels for increased imputation quality. Such invest- ments will be needed if we want to develop novel treatment strategies against osteoar- thritis fromwhich the whole global population could benefit. The first steps toward this goal have already been taken within the GO consortium. The consortium is ever increas- ing in size and including more and more diverse global populations. Fortunately, it also include cohorts with deep phenotyping information. Allowing for the development and use of phenotypes more accurately representing the deep complexity of osteoarthritis. Re-definition of osteoarthritis As stated above and throughout this thesis, the phenotyping of osteoarthritis is criti- cal for future osteoarthritis GWAS and research success. Especially if we want to move “from bench to bedside” . How we define osteoarthritis as a disease strongly determines the interpretation and power of a GWAS. Current and past osteoarthritis GWAS have pre- dominantly used “minimal phenotype” definitions, i.e. hospital diagnosed and self-re- ported osteoarthritis, possibly only identifying the “low-hanging fruit” of osteoarthritis GWAS[13, 17]. Exploring a wider range of biological/clinical relevant disease pheno- types, i.e., stratified and endophenotypes, will most likely lead to novel discoveries and/ or a more complete understanding of osteoarthritis genetics. Future osteoarthritis defi- nition and phenotypes need to embrace the heterogeneity in osteoarthritis. Although, this heterogeneity is well recognized[54], osteoarthritis is still described as a singular disease. Osteoarthritis should be referred to as a syndrome; multiple causes, pathways, tissues and pathologies all leading to the same clinical outcome: osteoarthritis[54]. The re-definition of osteoarthritis as syndrome can also be incorporated in GWAS pheno- type definitions: stratifying osteoarthritis symptoms (pain, stiffness, swelling, disabili- ty), main affected tissue (cartilage, bone, muscle etc.), or by underlying cause (traumat- ic, obesity) or predominant molecular pathway (vitamin K pathway). In addition, future phenotypes should also acknowledge the impact of other large osteoarthritis risk factors. The largest risk factor of osteoarthritis, is age, if the controls consist of young individuals (<50 years) they may still develop osteoarthritis at a later age. For GWAS research this might mean some genetic loci may be missed. However, age could also be incorporated into the osteoarthritis phenotype in GWAS for example by