Linkage studies aim to discover genomic regions that are co-transmitted with the disorder in families with several affected members. Systematic, family based genome-wide linkage studies are extremely successful in detecting rare variants with strong effects on the etiology of the disorder. This approach has been applied effectively to discover genetic factors underlying monogenic Mendelian diseases such as Huntington's disease (Gusella et al., 1983). However, this method is less effective in discovering genes that contribute only moderately to the etiology of a complex, heterogeneous disorder. In complex disorders, the presence of a specific vulnerability gene may not even be necessary. In their landmark paper, Risch and Merikangas (1996) calculated the number of families (affected sib pairs) required to demonstrate linkage. If gene effects are small, a dramatic reduction in the excess allele sharing between affected sibs will result, and very large samples will be necessary to demonstrate linkage. Meta-analyses of linkage scans attempt to overcome limitations in statistical power by combining data from various independent studies. These analyses have provided evidence for loci on 2q, 5q, 8p, 13q, and 22q (Badner and Gershon, 2002; Lewis et al., 2003; Ng et al., 2009).
