Cindy Boer

18 | Chapter 1.1 arthritis were inherited[37, 38]. it would not be It would not be until 1989, after the discovery of the DNA structure by Watson and Crick[29], that through linkage studies in families the first gene associated with osteoarthritis would be found. In genetic link- age studies inheritance of DNA regions, marked via genetic markers, is linked with the occurrence of the disease in a family. Using this method, a genomic region containing mutations (rare SNVs) in the COL2A1 gene was found to co-occur with osteoarthritis, in two families with high occurrence of premature osteoarthritis of several joints[39]. However, these mutations in the COL2A1 gene are very rare, while osteoarthritis is very common in the population, nor could the COL2A1 mutations explain the occurrence of other familial forms of osteoarthritis[40]. All indicating that osteoarthritis is also com- plex at the genetic level. Indicating that not one gene is involved in osteoarthritis risk but many genes are[40]. Since linkage studies are primarily useful to identify large effects of rare genetic variants for monogenetic (single gene) diseases, they are not suited for the study of complex diseases. In complex diseases, multiple genetic variations in multiple genes and their interaction with the environment determine the risk of disease. Since hun- dreds, if not thousands of variants can be involved, each individual variant will have a small effect on disease risk[41]. Osteoarthritis has both rare monogenetic forms, such as the COL2A1 mutations, and the much more common complex forms of the disease for which we now know that several hundreds of common variants with more subtle effects are involved in the genetic architecture of the disease ( Figure 4 ). Thus other methods are needed for the study of complex diseases, methods than can identify sub- tle effects of many hundreds of variants across the genome. Genome-wide association studies (GWASs) are such a method. Genome-Wide Association Studies In a genome-wide association study (GWAS) many millions of SNVs are examined whether a certain SNV occurs more frequently in individuals with the disease than in individuals without the disease[41]. The GWAS study design was made possible with the advent of cheap genotyping methods, where hundreds of thousands sites of genet- ic variation (SNVs) are measured on a single array. Through these measured SNVs the genotype of other SNVs within the same linkage(LD) block can be inferred by imputa- tion ( Figure 5) . Early arrays measured the genotype of hundreds of thousands of SNV uniformly distributed across the genome. However, this did not accurately or efficiently captured all LD blocks within the human genome, thus resulted in missing information on genetic variation in certain sections of the genome. Current arrays more efficiently