Cindy Boer

Summary | 281 7 threefold increased risk of osteoarthritis when using acenocoumarol, compared to non-users. In a popu-lation with European ancestry ~50% of the population is carrier of both these alleles, thus potentially exposing half of the acenocoumarol users in that population to a signif-icant increased risk of osteoarthritis. Thus, if the clinical indication allows, individuals in need of anticoagulation might be prescribed non- vitamin K inhibiting anticoagulants. In addition, the results of this chapter, validated the importance of MGP and vitamin K in osteoarthritis pathology, opening up the possibility to investigate vitamin K as thera-peutic target for osteoarthritis. In genome-wide association studies, the most important factors for success are phe- notype definition and sample size. Chapters 2 to 3, examined the effect of phenotype definition, in Chapter 4 sample size is examined. This was done by collaborating in the to date largest osteoarthritis genetics consortium: Genetics of Osteoarthritis (GO) consortium. The GO-consortium consists of over 20 different population studies from across the world, although predominantly of European ancestry, and contained in total 177,517 osteoarthritis cases and 649,173 controls. Chapter 4.1 presents the first results of the 11 osteoarthritis genome-wide association studies performed in the GO-consortium. In total 100 genetic loci associ- ated with osteoarthritis were discovered, of which 52 were novel and 48 were known osteoarthritis loci. Among these loci are, rare variants with large effects, variants with opposite direction of effects between phenotypes, characterise differences between weight-bearing and non-weight bearing joints and loci associated with all osteoarthri- tis phenotypes. Novel possible osteoarthritis target tissues could be identified as well as, genetic correlation of osteoarthritis with neuronal pathways and pain. Functional genomics data from primary patient tissues identified possible causal gene(s) for each locus and revealed possible shared underlying molecular mechanisms for comorbid cardiovascular diseases and osteoarthritis. All providing a new wealth of insight in to osteoarthritis pathology and highlight attractive targets for drug discovery and devel- opment. Osteoarthritis is a complex disease, and thus environmental factors also play a major role in the pathology. A novel environmental factor associated with disease is the human microbiome. The gut microbiota has been shown to play diverse roles in human health and disease although the underlying mechanisms have not yet been fully elucidated. Thus Chapter 5 investigated the possible role that the trillions of bacteria living inside