of anatomical joint involvement and bone remodelling responses to the disease, each with differing genetic contributions. Disease heterogeneity reduces the statistical power to detect genetic association and greatly decreases the estimates of risk attributed to genetic variation (Manchia et al. 2013). As the degree of heterogeneity increases (defined as the presence of within a case “non-cases” population), so does the minimum sample size required to achieve sufficient statistical power. For example, heterogeneity of 50% increases the required sample size by approximately three times (Manchia et al. 2013). In psychiatric disorders, the strategy of studying more homogenous sub-groups of individuals has been shown to significantly decrease the number of cases needed for adequately powered genetic studies (Jaitovich-Groisman & Cruceanu 2010; Davies 1986). Similarly, the investigation of the quantitative trait bone mineral density (BMD) in a GWAS for osteoporosis, confirmed substantial increases in power gained as a result of utilising a phenotype closer to the underlying biology of the disease (Estrada et al. 2012). Fifty-six loci associated with BMD at genome-wide significance, whereas only 6 associated at that same theshold with a clinical history of fracture (Estrada et al. 2012). Therefore, in spite of an inherent loss of sample size, the study of more homogenous, narrower phenotypes, contiguous with the biology of a disease, has the potential to lead to the discovery of many more variants behind individual mechanisms of disease development and progression. In addition, the effect sizes of those marginally significant variants identified in GWAS may be larger if they were examined in more homogeneous samples (Manchia et al. 2013; Evangelou et al. 2011), further closing the gap of missing heritability. 1.5: The Genetic Aetiology of Osteoarthritis Twin studies estimate the genetic contribution to susceptibility of radiographic OA at the hip and knee in women is between 39% and 70% (MacGregor et al. 2008). Strength of heritability is site-specific with hand and hip OA more heritable than knee OA (MacGregor et al. 2008; Loughlin, 2005). Individual radiographic features of OA (e.g. osteophytes and joint space narrowing) differ in their heritability both within and
of anatomical joint involvement and bone remodelling responses to the disease, each with differing genetic contributions. Disease heterogeneity reduces the statistical power to detect genetic association and greatly decreases the estimates of risk attributed to genetic variation (Manchia et al. 2013). As the degree of heterogeneity increases (defined as the presence of “non-cases” within a case population), so does the minimum sample size required to achieve sufficient statistical power. For example, heterogeneity of 50% increases the required sample size by approximately three times (Manchia et al. 2013). In psychiatric disorders, the strategy of studying more homogenous sub-groups of individuals has been shown to significantly decrease the number of cases needed for adequately powered genetic studies (Jaitovich-Groisman & Cruceanu 2010; Davies 1986). Similarly, the investigation of the quantitative trait bone mineral density (BMD) in a GWAS for osteoporosis, confirmed substantial increases in power gained as a result of utilising a phenotype closer to the underlying biology of the disease (Estrada et al. 2012). Fifty-six loci associated with BMD at genome-wide significance, whereas only 6 associated at that same theshold with a clinical history of fracture (Estrada et al. 2012). Therefore, in spite of an inherent loss of sample size, the study of more homogenous, narrower phenotypes, contiguous with the biology of a disease, has the potential to lead to the discovery of many more variants behind individual mechanisms of disease development and progression. In addition, the effect sizes of those marginally significant variants identified in GWAS may be larger if they were examined in more homogeneous samples (Manchia et al. 2013; Evangelou et al. 2011), further closing the gap of missing heritability. 1.5: The Genetic Aetiology of Osteoarthritis Twin studies estimate the genetic contribution to susceptibility of radiographic OA at the hip and knee in women is between 39% and 70% (MacGregor et al. 2008). Strength of heritability is site-specific with hand and hip OA more heritable than knee OA (MacGregor et al. 2008; Loughlin, 2005). Individual radiographic features of OA (e.g. osteophytes and joint space narrowing) differ in their heritability both within and
Final-PhD-after-corrections-thesis-final.docx