Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

292 K. Merikangas and K. YuMarkers in the candidate region identified by linkage analysis can be used tonarrow the location of the disease gene through linkage disequilibrium analysis.Linkage disequilibrium is a population association between two alleles at differentloci, and occurs when the same founder mutation exists in a large proportion ofaffected subjects in the population studied. Usually, the closer the marker is to thedisease locus, the greater the proportion of affected subjects who carry the identicalallele at the marker (Risch, 2000). However, in measuring the strength of linkagedisequilibrium for a given marker, it is also important to select unaffected controlsubjects from the same population, because an allele shared among affectedsubjects may also be common in the general population and thus shared by chancerather than due to proximity to the disease locus (Risch, 2000).Review of empirical evidenceThe initial enthusiasm generated by early claims of linkage between bipolardisorder and DNA markers including Xq (Baron et al., 1987; Mendlewicz et al.,1987; Lucotte et al., 1992) and 11p (Egeland et al., 1987) was diminished bysubsequent non-replications (Risch and Botstein, 1996). Numerous linkage studiesof bipolar disorder have subsequently been reported to regions on all but sixchromosomes (Straub et al., 1994; Pekkarinen et al., 1995; Stine et al., 1995;Blackwood et al., 1996; Detera-Wadleigh et al., 1996, 1999; Freimer et al., 1996;McMahon et al., 1997; Moldin, 1997; Smyth et al., 1997; Ewald et al., 1998a, b;Aita et al., 1999; Kelsoe, 1999; Morissette et al., 1999; Kelsoe et al., 2001).Table 13.3 presents a summary of genome-wide linkage studies of bipolar disorderupdated from a recent review by Prathikanti and McMahon (2001). Based on atotal of 3538 bipolar I disorder scans in affected subjects from 1119 pedigreesreported in 20 samples, the authors conclude that no two studies conclusivelyimplicate the same region. However, suggestive findings emerged for two loci(i.e., 4p12–13 and 13q31–33). The most striking conclusion was that no two studiesemployed identical ascertainment procedures and there was substantial diversityin sampling and methods. In conclusion, sufficient ambiguities exist to give pausein considering any of these linkage results as unambiguously replicated (Goldinet al., 1997; Reus and Freimer, 1997; Rice et al., 1997; DeLisi et al., 2000; Altmülleret al., 2001; Craddock and Jones, 2001). More recently, McMahon et al. (2001)reported replication of the suggestive finding reported earlier by Nöthen et al.(1999). The demonstration of the low power of existing linkage studies by Rischand Merikangas (1996) generated a spate of association studies of mood disorders,particularly those employing within-family controls (Merikangas et al., 2002b).Some other features of mood disorders that complicate genetic analyses aredescribed below.