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

290 K. Merikangas and K. YuIn genetic case-control studies, the most likely source of confounding is ethnicitybecause of differential gene and disease frequencies in different ethnic subgroups.Aside from confounding, association studies are particularly prone tofalse-positive findings due to multiple testing without correction and the low priorprobability of a gene–disease association (Wacholder et al., 2000). In addition,there is a strong publication bias against reports of negative association studies(Risch and Merikangas, 1996). The latter problem can be resolved in part by theuse of much higher -levels (i.e., false-positive error rates) in association studies(Hirschhorn et al., 2002).The loci for several biochemical parameters that are suspected to be involvedin either etiology or outcome of the psychiatric disorders have been identified. It isimportant to note that many of these assignments are based upon a single study,and replication is clearly necessary. Identification of new loci is occurring at sucha rapid rate that it is necessary to update the human map monthly. Application ofthis methodology to psychiatric disorders may be particularly fruitful in identifyingmajor genes that are segregating in informative families.Review of empirical evidenceGreat emphasis has been placed on the association study of various affectivespectrum disorders, focusing mostly on polymorphisms. From these studies, nofunctional differences between the alleles have been described (Johansson et al.,2001). The most noted exception is an insertion/deletion polymorphism located inthe promoter region of the serotonin transporter gene (5-HTTLPR), reported toaffect the expression of the transporter (Lesch et al., 1996), but there are also nonreplicationsof these results (Rees et al., 1997; Ohara et al., 1998a; Frisch et al., 1999;Seretti et al., 1999). The 5-HTTLPR polymorphism has also been associated withclinical subtypes of depression, including SAD and seasonality (Rosenthal et al.,1998; Sher et al., 1999), but the findings have not been able to be replicated in twosubsequent studies (Johansson et al., 2001). Other polymorphisms include anamino acid substitution in catechol-O-methyltransferase (COMT) affecting theenzymatic activity (Lachman et al., 1996a, b), which has been linked to bipolardisorder, including the rapid-cycling bipolar disorder subtype, and unipolardepression (Li et al., 1997; Kirov et al., 1998; Ohara et al., 1998b). A repeatpolymorphism in the promoter region of a monoamine oxidase A (MAOA)gene has also been reported to influence the transcriptional activity (Kunugiet al., 1999). Unfortunately, conflicting results have been found for both polymorphisms(Biomed European Bipolar Collaborative Group, 1997; Frisch et al.,1999; Kunugi et al., 1999; Schulze et al., 2000).