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

297 Challenges in the genetics of bipolar disorderfor most human disorders. Phenomena such as penetrance (probability of phenotypicexpression among individuals with susceptibility gene), variable expressivity(degree to which susceptible individuals express components of genotype),gene–environment interaction (expression of genotype only in the presence ofparticular environmental exposures), pleiotropy (capacity of a gene to manifestsimultaneously several different phenotypes), and genetic heterogeneity (differentgenes leading to indistinguishable phenotypes) have been demonstrated for severalhuman disorders for which susceptibility genes have been identified.Two of these phenomena that have been of particular concern for geneticnosology are genetic heterogeneity, or one from many, and pleiotropy, or manyfrom one. These two situations are reflected in the nosologic tension betweenlumping and splitting, as described by Victor McKusick in his review of historicaldevelopments in genetic nosology (1973). With increasing specialization in medicine,there has been a tendency to split categories excessively. The lumpers havecorrected the oversplitting; but recent advances in genetics have led to a new waveof ‘‘better-founded splitting’’ based on an increased ability to detect subtlerphenotypic similarity but genotypically heterogeneous conditions.Gene–environment interactionGene–environment interaction characterizes a broad range of human diseases suchas cancer and birth defects. Not only is the expression of genes modified by theenvironment, but there is now also substantial evidence to indicate that numerousenvironmental factors may actually alter the genotype. Francis and colleagues (1999)have shown that maternal behavior mediates stress reactivity in adulthood and isassociated with future maternal behavior among offspring. Genes may also beinvolved in the response or resistance to purely environmental agents such as diet,stress, exercise, drugs, and nutritional deficiencies (Omenn and Motulsky, 1978).The methods of genetic epidemiology are designed specifically to identify gene–environment interactions (Ottman, 1995; Yang and Khoury, 1997).The lack of validity of diagnostic categories is therefore by no means unique topsychiatry. Similar to other domains of complex disorders, the major impedimentsto the establishment of validity of the classification of psychiatric disordersare: the unreliability of measurement (of both diagnoses and markers); the lack ofspecificity of risk factors and biologic markers; and the lack of one-to-onecorrespondence between the phenotype and genotype likely attributable to bothetiologic and phenotypic heterogeneity and gene–environment interaction. Thewell-known steps for validating phenotypes recently reiterated by Tsuang et al.(1993) include the following guidelines: specificity, state of independence, heritability,familial association, co-segregation, and biological and clinical plausibility.