There are two main types of genetic association studies: population-based case-control studies and family-based studies. Family-based association studies are often most efficiently aimed at finding rare variants underlying rare conditions or rare sub-phenotypes of a common condition. Their design is not the focus of this protocol. Population-based (defined here as non-family based) case-control studies have become the most popular design to find common polymorphisms thought to underlie complex traits (also termed ‘common disease common variant’ hypothesis’) 5. They can be hypothesis-driven candidate gene (CG) studies, focussing on a particular gene or area of the genome, or can involve genome-wide association (GWA) analyses conducted without prior hypotheses. Until recently, the success rate of candidate gene case-control studies was very poor. To illustrate, a review in 2002 of 603 published disease-genetic variant associations found that only 6 appeared to be independently replicated 6. Some investigators have interpreted this as evidence that most - if not all - complex traits are not caused by common genetic polymorphisms but by multiple rare ones 7, for which population-based case-control studies have little or no POWER
