Cindy Boer

General Discussion | 259 6 ▲ Figure 2: All known osteoarthritis stratified and endophenotype associated loci. In bold are the variants mentioned in this thesis. Only genome-wide significant associated (p-value≤5*10 -08 ) are included, for variants in high LD(r 2 ≥0.6, D’≥0.6) only one variant is depicted. KLsum: sum of Kellgren- Lawrence OA severity score, mJSW: minimum joint space width, DDH: developmental dysplasia of the hip, bone area as measured by DXA scan, shape: shape of the joint measured on radiographs. Phenotyping: Endophenotypes Another method to increase GWAS power and interpretation is the use of endopheno- types, phenotypes more closely related to the underlying genetics and/or pathology than to the end-stage disease itself. In Chapter 2.1 cartilage thickness in the hip joint, measured by minimum joint space with (mJSW), was used as an endophenotype for osteoarthritis. Using mJSW over the dichotomous definition of hip osteoarthritis has as main advantage that mJSW focuses on a single part of the joint, the joint space width, as a measure of cartilage thickness. The mJSW can be measured in all individuals, whether or not they have osteoarthritis creating a quantitative measure with greater power than that of the dichotomous trait[17]. Additionally, as GWAS interpretation is dependent on phenotype definition[13, 14, 19], endophenotypes, by their focus on a single underlying characteristic or tissue linked to the disease, helps with interpretation of the observed association with the minimal phenotypes. Also, for known disease variants, endophenotypes can help to elu- cidate their biological role: in which pathway or pathology these variants may play a role. However, this also means that possibly not all SNVs identified with an endopheno- type are automatically associated with end-stage clinical disease. Still, endophenotypes are a very successful method to increase GWAS power, to identify underlying mecha-