Flow chart of current strategies used to identify novel disease genes. This scheme outlines strategies for identifying mutations and/or polymorphisms causing or predisposing to disease. Candidate genes are chosen based on genetic linkage data and/or known or hypothesized pathobiological relevance to disease mechanisms. This procedure is referred to as the “candidate gene approach.” An alternative and inherently similar strategy is based on the detection of formerly unknown genes/proteins according to genetic linkage data and is referred to as “positional cloning.” Dashed lines indicate “shortcuts” allowing the definition of a novel disease gene based on the genetic evidence alone, e.g., APOE-ε4 in AD, of which the precise functional consequences remain unknown despite an established genetic role. Note that there are examples of genes/mutations with reduced penetrance or minor risk effects (red boxes) within bona fide disease genes (e.g., certain mutations in PSEN1 in AD).