Cindy Boer

General Introduction | 21 1.1 SNVs associated with complex diseases, GWASs need very large sample sizes to have the statistical power to robustly identify associated genetic variations. In sum, a GWAS uses imputed genotype information of millions of SNVs to identi- fy genetic associations in large sample sizes. SNVs are included into the GWAS, without any a-priori selection, all possible SNVs that can be imputed are included. This is also termed “hypothesis-free”. However, contrary to popular belief, GWASs are not truly hy- pothesis-free, as GWASs assume that the disease or investigated trait has a genetic com- ponent[41]. This is why GWAS has proven to be a very successful method for finding genetic variation associated with complex disease, such as osteoarthritis [41] ( Figure 4 ) and, not so much for being a “dog-person ”[46]. Epigenetics: beyond genetic complexity A GWAS identifies SNVs or a genomic region (locus) to be associated with a disease or trait, it only very rarely directly identifies genes. Only through many subsequent steps in downstream bio-informatics and functional studies to test the candidate genes in the region associated genes can be identified. However, it is not always very easy to determine how a SNV could affect a gene or which gene it would affect, especially with- in the context of a disease or trait. SNVs can be located anywhere in the genome, and only 2% of the genome consists of coding DNA. However, the 98% non-coding DNA is not without function and is thought to have several important roles including in gene regulation.: the regulation of the 2% coding DNA, via gene regulatory sequences. These are stretches of DNA sequences that are involved in the regulation of gene expression. Usually DNA binding proteins, such as transcription factors (TF), can bind to these DNA sequences and regulate gene expression. Such gene regulatory sequences can be identi- fied in the DNA by examining where these TF bind the DNA, or by examining epigenetic modifications. Epigenetic modifications are modifications to the DNA base pairs and DNA bind- ing proteins that do not alter the DNA sequence, but do affect gene activity and expres- sion. Many such epigenetic modifications are known, these include DNA methylation and histone modifications. How these epigenetic modifications can be used for GWASs is detailed in Chapter 1.2. Epigenetics is also a mechanism by which the environment can affect gene activity and regulation, and, thus, influence disease risk. What the role is of epigenetics in skeletal disorders such as osteoarthritis is also detailed in Chapter 1.2. Throughout this thesis, epigenetics is used in GWAS, in order to gain more insight into osteoarthritis pathology, and ultimately provide novel treatment options. Chapters 2-4 use epigenetics for GWAS interpretation and in Chapter 3 these GWAS interpretations even lead to possible clinical implications for osteoarthritis patients.